Link Found Between Agent Orange Exposure and Myeloproliferative Neoplasms in Veterans

Posted on May 31, 2023May 31, 2023 by mpn_admin

By Rob Dillard

US veterans who were exposed to Agent Orange (AO) have an increased risk of myeloproliferative neoplasms (MPNs), bleeding, arterial thrombosis (AT), and venous thrombosis (VT), according to an analysis that will be presented at the 2023 American Society of Clinical Oncology Annual Meeting.

AO is a chemical herbicide that was weaponized and heavily used during the Vietnam War. The chemical is associated with the development of sarcomas and B-cell lymphomas, but, until now, less has been known about its link to MPNs, bleeding, AT, and VT.

To conduct their analysis, lead author Andrew Chua Tiu and colleagues used the VA Informatics and Computing Infrastructure database to identify 95,768 patients with MPN and any AT, VT, and bleeding events.

According to the results, there was a notable correlation between AO exposure and the development of MPNs (odds ratio, 1.61; 95% CI, 1.57-1.65; P<.0001). Specifically, the researchers observed that compared with patients with MPNs who were not exposed to AO, patients with MPNs who were exposed to AO had higher rates of AT (36.0% vs 28.2.%), higher rates of AT (28.7% vs 24.0%), and more bleeding events (41.2% vs 39.0%).

“This is the largest database evaluating MPNs, thrombosis, and bleeding in veterans exposed to AO. There is an association of increased risk of development of MPNs, increased AT, and increased bleeding with AO exposure,” the researchers concluded. They added that further studies “including JAK2 mutation, [clonal hematopoiesis of indeterminate potential], and cardiovascular risk factors will be needed to evaluate contribution to thrombosis and bleeding risk.”

Source: Tiu AC, McKinnell Z, Liu S, et al. Association of Agent Orange and myeloproliferative neoplasms, thrombosis, and bleeding among veterans. Abstract #7011. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

Study Assesses Outcomes of Patients With AF and Myeloproliferative Neoplasms

Posted on May 31, 2023May 31, 2023 by mpn_admin

By Rob Dillard

Patients admitted for atrial fibrillation (AF) who have myeloproliferative neoplasms (MPNs) have an increased risk of any-cause and bleeding-related readmissions, according to a study that will be presented at the 2023 American Society of Clinical Oncology Annual Meeting.

Individuals with MPNs, essential thrombocythemia, polycythemia vera, and primary myelofibrosis face an increased risk of cardiovascular disease, including atrial thrombosis (AT). “[AF] is also associated with increased risk of AT and often coexists with MPN. However, thrombotic and bleeding outcomes in patients with MPN compared with those without have not been thoroughly investigated,” the investigators noted.

In this analysis, first author Orly Leiva and colleagues assessed 468,094 patients with AF and 1617 patients with a history of MPN in 2017 and 2018. Patients of interest were 18 years of age and older and were identified using the National Readmission Database. The study’s key end points were 30-day and 90-day any-cause, AT-related (including stroke, myocardial infarction, arterial thromboembolism), and bleeding-related readmissions.

According to the findings, patients with MPN had an increased risk of 30-day all-cause (hazard ratio [HR], 1.72; 95% CI, 1.70-1.74), AT-related (HR, 1.45; 95% CI, 1.38-1.53), and bleeding-related (HR, 2.21; 95% CI, 2.01-2.44) readmissions. Moreover, researchers found that patients with MPN had an increased risk of 90-day any-cause (HR, 1.38; 95% CI, 1.37-1.40) and bleeding-related (HR, 1.76; 95% CI, 1.65-1.88) but not AT-related (HR, 1.03; 95% CI, 0.99-1.08) readmissions.

“Among patients admitted for AF, MPN is associated with increased risk of 30-[day] and 90-[day] any-cause and bleeding readmissions and 30-[day] AT readmissions despite similar CHA₂DS₂-VASC and HAS-BLED risk scores,” the researchers concluded. They added that further studies “are needed to identify risk factors for bleeding and AT in patients with MPN and AF and improve on current risk scores, which do not include MPN status.”

Source: Leiva O, How Chi-Joan, Brunner A, Grevet J, Hobbs G. Outcomes of patients with a myeloproliferative neoplasm and atrial fibrillation. Abstract #7070. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

Abbas Looks at the Use of Ruxolitinib and Fedratinib in Myelofibrosis

Posted on May 31, 2023May 31, 2023 by mpn_admin

May 30, 2023

Targeted Oncology Staff

In the second part of a live discussion on treating patients with myelofibrosis, Jonathan Abbas, MD, led a talk on the impact of ruxolitinib for these patients and where physicians stand with the use of fedratinib.

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats and abdominal pain/fullness lasting 4 months; she also reported increased bruising and unexplained weight loss. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed she was negative for a JAK2 V617F or CALR mutation. Her karyotype was 46XX and a bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis.

A blood smear revealed leukoerythroblastosis and she was diagnosed with primary myelofibrosis with a risk score of Dynamic International Prognostic Scoring System intermediate-2 and was also considered intermediate risk on the MIPSS70 score. However, the patient is not interested in transplant and a decision was made to initiate ruxolitinib (Jakafi).

DISCUSSION QUESTION

What data demonstrates the efficacy of ruxolitinib for a patient like this?

JONATHAN ABBAS, MD: [In the final analysis of the phase 1b EXPAND dose finding study (NCT01317875)], in patients who started with a lower dose of ruxolitinib, there was some thrombocytopenia [at 40%], but platelets were pretty much OK with only 25% of patients with decreasing platelets and then anemia was acceptable [at 25% as well].¹ So you can still have efficacy with some acceptable cytopenias is the take home if you put the effort into the ruxolitinib dosing.

In looking at spleen response [of these patients] at lower doses because of the thrombocytopenia, we are still seeing patients have tremendous clinical improvement, and spleen response. In their total symptom scores [TSS], looking at response, you can definitely see improvement [there as well].

In patients with profound anemia [in the COMFORT-I study (NCT00952289)], I don’t know if there’s a tremendous amount of conclusions there other than the ruxolitinib patients, regardless of having anemia, did very well whereas anemic patients who were on best available therapy or on placebo, not surprisingly, are the ones who [had lower efficacy].²

GREGG SHEPARD, MD: The main problem I have with a lot of my patients is anemia becoming more emergent during treatment and becoming more transfusion dependent over time. I dose reduce and they’re on 10 mg once a day, or 5 mg twice a day, and we saw the data previously where efficacy is not great when the dose is that low. So, I don’t know that’s just a struggle [I have].

If the efficacy is not there at less than 10 mg twice a day, then do you just stop the drug completely, or give people supportive care, or look for a trial, or try to increase the dose back up to 10 or 15 mg twice a day and just give them more transfusions?

ABBAS: If you put someone on a Janus kinase [JAK] inhibitor and they’re doing great and symptoms are then improving, but now you’re driving anemia into a transfusion-dependent state so you dose reduce. Now you’re starting to see possibly a loss of clinical response that you had to dose reduce so much, even if the anemia might be getting better. What’s our next step there? Are we offering patients growth factor support when we’re treating them? Is that a scenario people have run into?

IBRAHIM NAKHOUL, MD: We’ve frequently had to use erythropoiesis stimulating agents (ESAs), but it’s not been all that successful.

JACK ERTER, MD: I’ll echo that. I have tried ESA support, and things of that nature, with no benefit.

ABBAS: I’m with you. I’ve tried it and I can’t say it’s ever been terribly successful. While we’re on this topic, 1 thing that’s out there which might not be a too off label to try if you want, is luspatercept [Reblozyl]. Luspatercept in some early studies did have some nice effects on anemia in myeloproliferative neoplasms and is in some later-phase trials.³ So that’s a drug that might be able to provide some better hematologic support for these patients, but…that’s a potential file-away for later options.

DISCUSSION QUESTION

How has data from the JAKARTA trial (NCT01437787) impacted your practice?

ABBAS: The JAKARTA trial randomly assigned fedratinib [Inrebic] or placebo to patients with either primary or secondary myelofibrosis.⁴ Spleen volume reduction was excellent with a tremendous…number of people who clinically benefited [with 37% vs 1% in the placebo arm], so you can see how well the fedratinib arm did.

Now, we do see some gastrointestinal [GI] toxicities [at all adverse event (AE) grades] with fedratinib [like diarrhea (66%)]. We don’t like cross-trial comparisons, but we live off it anyways, and I think there is a little more GI signaling in fedratinib [than ruxolitinib]. Then we saw degrees of anemia [74%] and thrombocytopenia [47%] comparable with what we’ve seen with ruxolitinib.

The rare AEs with fedratinib included 1 case of Wernicke encephalopathy on treatment, 1 case with an unknown origin, and 2 cases after data lock. This did lead to a black box warning for this, so you do want to make sure the thiamine deficiency isn’t something you want to worry about in a fedratinib patient. Have any of you used fedratinib?

MICHAEL BYRNE, DO: I’ve used it. My experience with it was not positive. I thought it was toxic and not effective, so I’ve not been in a rush to use it.

ABBAS: In my clinical experience…it was the exact same experience as you.

SHEPARD: I have a patient currently on it who’s in the waiting period to get an allogeneic transplant because they failed ruxolitinib and they were off all therapy for a while, just on supportive care. We put her on fedratinib in hope that it would get better…but I have not seen any improvement so far. The patient’s still anemic and transfusion dependent, tolerating it fine, just no better.

ABBAS: What was the ruxolitinib failure? Was it a non-response, was it due to non-tolerability, or both?

SHEPARD: It was interesting. It was a patient who was put on it because they had post- polycythemia vera myelofibrosis and primarily symptomatic with anemia, but never had symptomatic splenomegaly at all. They were put on ruxolitinib, and it did not help their anemia get any better, so [they were] taken off it. It was the same thing with fedratinib. So, now we’re waiting for a possible allogeneic transplant for them.

ABBAS: That’s great. How do we monitor the patient from our case…do people do serial imaging?

ERTER: In this specific disease, yes, I think the splenomegaly is so obvious that I don’t think there’s a huge advantage to getting ultrasounds or CT scans compared with a lot of other diseases we treat.

^References

^{1. Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. Haematologica. 2019;104(5):947-954. doi:10.3324/haematol.2018.204602}

^{2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):799-807. doi:10.1056/NEJMoa1110557}

^{3. Kubasch AS, Fenaux P, Platzbecker U. Development of luspatercept to treat ineffective erythropoiesis. Blood Adv. 2021;5(5):1565-1575. doi:10.1182/bloodadvances.2020002177}

^{4. Pardanani A, Tefferi A, Masszi T, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021;195(2):244-248. doi:10.1111/bjh.17727}

Luspatercept Nearly Doubles Likelihood of Transfusion Independence in Lower-Risk MDS

Posted on May 30, 2023May 30, 2023 by mpn_admin

May 25, 2o23

Caroline Seymour

Luspatercept-aamt (Reblozyl) led to a higher rate of sustained transfusion independence compared with erythropoiesis stimulating agents (ESAs) in patients with ESA-naïve, lower-risk myelodysplastic syndrome (MDS), according to data from the phase 3 COMMANDS trial (NCT03682536) presented in a press briefing prior to the 2023 ASCO Annual Meeting.^1,2

In the intention-to-treat population, 58.5% of patients who received luspatercept achieved transfusion independence for at least 12 weeks with hemoglobin increase of at least 1.5 g/dL compared with 31.2% of patients who received epoetin alfa, meeting the primary end point of the study (P < .0001).

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs in transfusion-dependent lower-risk MDS, [and this should be] considered a paradigm shift in the treatment of lower-risk MDS–associated anemia,” Guillermo Garcia-Manero, MD, lead study author and professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data.

Anemia is one of the main symptom burdens for patients with MDS, and chronic anemia and transfusion dependence in lower-risk MDS presents challenges in the clinic, often leading to increased risk of death compared with patients who are transfusion independent. Additionally, standard treatment with ESAs is associated with modest activity, leaving an unmet need for treatment in this population.

Luspatercept is a monoclonal antibody that affects the TGF-beta pathway, leading to increased erythrocytosis. The agent is currently indicated for the treatment of patients with ring sideroblast–positive, lower-risk MDS with progression on or ineligibility for an ESA.

COMMANDS was an open-label, global, randomized trial that enrolled patients at least 18 years of age with Revised International Prognostic Scoring System very low–, low-, or intermediate-risk MDS with or without ring sideroblasts by World Health Organization 2016 criteria with less than 5% blasts in bone marrow. In addition, patients had to have required between 2 and 6 packed red blood cell units per 8 weeks for at least 8 weeks prior to randomization, endogenous serum erythropoietin less than 500 U/L, and lack of prior exposure to ESA therapy.

Patients were stratified by baseline serum erythropoietin level (≤200 U/L vs >200-500 U/L), baseline red blood cell transfusion burden (<4 U/8 weeks vs ≥4 U/8 weeks), and ring sideroblast status (positive vs negative).

The primary end point of the study was the rate of red blood cell transfusion independence for 12 weeks or more with concurrent mean hemoglobin increase of at least 1.5 g/dL.

Eligible patients were randomly assigned 1:1 to receive 1.0 mg/kg of subcutaneous luspatercept every 3 weeks titrated up to 1.75 mg/kg (n = 178) or 450 IU/kg of subcutaneous epoetin alfa every week titrated up to 1050 IU/kg (n = 178). Patients were evaluated for response at day 169 and every 24 weeks thereafter. Treatment was discontinued in the absence of clinical benefit or disease progression per International Working Group criteria. After treatment was completed, patients were followed for other malignancies, high-risk MDS or acute myeloid leukemia (AML) progression, subsequent therapy, and survival for 5 years from the first dose of study treatment of 3 years from the last dose, whichever occurred last.

The median duration of treatment was 41.6 weeks (range, 0-165) with luspatercept vs 27.0 weeks (range, 0-171) with epoetin alfa.

Additional results demonstrated higher rates of transfusion independence with luspatercept regardless of stratification criteria. Moreover, patients experienced improved rates of transfusion independence with luspatercept regardless of SF3B1 mutation status.

Notably, treatment with luspatercept led to prolonged transfusion independence regardless of ring sideroblast status. “Luspatercept provided clinical benefit regardless of patient subgroups,” Garcia-Manero added.

In all patients, the median duration of transfusion independence for at least 12 weeks was 126.6 weeks (95% CI, 108.3–not evaluable [NE]) with luspatercept vs 77.0 weeks (95% CI, 39.0-NE) with epoetin alfa (HR, 0.456; 95% CI, 0.260-0.798). In ring sideroblast–positive patients, the median durations were 120.9 weeks (95% CI, 76.4-NE) and 47.0 weeks (95% CI, 36.6-NE) with luspatercept and epoetin alfa, respectively (HR, 0.626; 95% CI, 0.361-1.085). In ring sideroblast–negative patients, the median durations were NE (95% CI, 46.0-NE) and 95.1 weeks (95% CI, 35.3-NE), respectively (HR, 0.492; 95% CI, 0.148-1.638).

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 92.1% (n = 164) of patients in the luspatercept arm vs 85.2% (n = 150) of patients in the epoetin alfa arm.

“The toxicity profile was consistent with previous clinical experience,” Garcia-Manero stated.

Any-grade hematologic toxicities in the luspatercept and epoetin alfa arms, respectively, included anemia (9.6% vs 9.7%), thrombocytopenia (6.2% vs 1.7%), neutropenia (5.1% vs 7.4%), and leukocytopenia (1.1% vs 1.7%). Any-grade TEAEs of interest include fatigue (14.6% vs 6.8%), diarrhea (14.6% vs 11.4%), peripheral edema (12.9% vs 6.8%), asthenia (12.4% vs 14.2%), nausea (11.8% vs 7.4%), dyspnea (11.8% vs 7.4%), and thromboembolic event (4.5% vs 2.8%).

Moreover, patients in the luspatercept arm experienced fewer progressions to high-risk MDS and AML compared with patients in the epoetin alfa arm, at 2.8% (n = 5) and 2.2% (n = 4) vs 4.0% (n = 7) and 2.8% (n = 5), respectively. Thirty-two fatalities occurred in both arms.

“In patients with anemia with lower-risk MDS who depend on red blood cell transfusions, luspatercept almost doubles the number of people who achieve independence from transfusions for a period lasting 12 weeks or more, when compared with epoetin alfa, a current standard of care treatment. Luspatercept may be an effective first treatment option for anemia associated with lower-risk MDS,” Olatoyosi Odenike, MD, FASCO, a professor of medicine and director of the Leukemia Program at University of Chicago Medicine, stated in a news release.

References

Garcia-Manero G, Platzbecker U, Santini V, et al. Efficacy and safety results from the COMMANDS trial: A phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent (ESA)‑naive transfusion-dependent (TD) patients (pts) with lower‑risk myelodysplastic syndromes (LR-MDS). J Clin Oncol. 2023;41(suppl 16):7003. doi:10.1200/JCO.2023.41.16_suppl.7003
Luspatercept improves anemia and reduces reliance on blood transfusions for people with lower-risk myelodysplastic syndromes. News release. ASCO. May 25, 2023. Accessed May 25, 2023. https://old-prod.asco.org/about-asco/press-center/news-releases/luspatercept-improves-anemia-and-reduces-reliance-blood

Adoption of Mediterranean diet shows promise in easing symptoms for myeloproliferative neoplasm patients

Posted on May 30, 2023May 30, 2023 by mpn_admin

By Dr. Priyom Bose PhD

May 25, 2023

Myeloproliferative neoplasm (MPN) represents a group of inflammatory diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPNs are linked to hematologic malignancies and are characterized by clonal outgrowth of hematopoietic cells with an acquired mutation in JAK2.

Multiple studies have shown that the Mediterranean diet positively impacts diseases associated with chronic subclinical inflammation. In addition to the Mediterranean diet, the gut microbiome also plays a crucial role in improving hematologic disorders.

A new study published to the medRxiv* preprint server assesses the feasibility of an education-focused Mediterranean diet intervention among MPN patients.

Background

Clinical manifestations of MPN include abnormal blood counts, thrombosis, and transformation to acute leukemia. One of the key characteristic features of MPN is increased plasma cytokines.

Chronic inflammation leads to abnormal blood count. Although JAK inhibitors alleviate MPN symptoms, these drugs are associated with certain risks, such as immunosuppression, skin cancer, and weight gain.

The recent National Comprehensive Cancer Network (NCCN) guidelines for MPN proposed several interventions to reduce symptom burden, irrespective of the prognosis scoring category.

Since many MPN patients do not meet the criteria for a cytoreductive agent, their symptoms are maintained without specific interventions. As a result, the quality of life of these patients is adversely affected due to the inability to limit disease progression.

Lifestyle modification, mainly through diet, can reduce inflammation. For example, a healthy diet high in anti-inflammatory agents can improve symptom burden among MPN patients. Adherence to this type of diet can decrease inflammation and significantly delay or prevent disease progression.

The Mediterranean diet is a primarily plant-based diet, which is associated with the consumption of nuts, extra virgin olive oil (EVOO), vegetables, fish, fruits, legumes, and whole grain products. Controlling inflammation through nutrition is a low-risk therapeutic approach to mitigate the burden of symptoms for MPN patients.

About the study

The primary aim of the current study was to determine the willingness of MPN patients to engage in dietary education to manage symptom burden. Participants were randomly assigned to either a standard U.S. Dietary Guidelines for Americans (USDA) group or Mediterranean diet group. Both groups received separate but equal education through written dietary resources and registered dietician counseling.

Patients were followed for adherence, feasibility, and symptom burden assessments. To explore changes in the gut microbiome and inflammatory biomarkers, biological samples were collected at four distinct time points throughout the 15-week study period.

Study findings

MPN patients found the Mediterranean diet program equally easy to follow as a program based on the U.S. Guidelines for Americans. Over 80% of participants in the Mediterranean diet group could maintain good adherence throughout the intervention period as compared to less than 50% in the USDA group. This serves as evidence that, with proper dietician counseling and written curriculum, MPN patients can feasibly adopt a Mediterranean diet.

MPN patients can adopt a Mediterranean eating pattern with dietician counseling and education. (A) Percentage of participant with MEDAS scores ≥8 at each time point with orange shaded area depicting the active intervention period (B) Participant responses to feasibility question during active intervention period (C) HEI-2015 was calculated from each 24 hour diet recall, and scores for each participant were averaged for the pre-intervention (weeks 1-2), active intervention (weeks 3-12), and post-intervention (weeks 13-15) period. Data shown represents median with interquartile range.

In MPN, an important goal is to target symptoms, as symptoms can significantly affect the patient’s’ quality of life. In the USDA group, 31% of the cohort exhibited more than a 50% reduction in the MPN-Total Symptom Score (TSS) at 15 weeks, whereas 53% of the Mediterranean diet group exhibited more than a 50% reduction in the MPN-TSS.

As compared to the USDA diet, the Mediterranean diet had a better effect on alleviating MPN symptoms. The length of the diet intervention and intensity are important factors in alleviating MPN symptoms.

Changes in symptom burden during study. (A) waterfall plots of percentage change in MPN-SAF (MPN-TSS) at each week compared to baseline (baseline defined as average MPN-TSS of weeks 1 and 2) (B) Raw change in specific symptoms at each week compared to baseline (mean±SD).

Future outlook

Both diets investigated in the current study led to a reduction in MPN symptom burden. Thus, these findings demonstrate that a 10-week intervention is sufficient to detect a change in symptoms.

In the future, a longer intervention period is required to assess whether improvements in symptoms continue. A longer intervention period would also help detect people with delayed symptom improvement.

The current analysis highlights that MPN symptoms may stem from different root causes; therefore, some symptoms change quickly compared to others. Due to the small sample size, a decrease in the inflammatory cytokines could not be detected. Therefore, future studies with a larger cohort are needed to elucidate how diets impact inflammatory cytokine levels.

Journal reference:

Preliminary scientific report. Luque, M. F. L., Avelar-Barragan, J., Nguyen, H., et al. (2023) The NUTRIENT Trial (NUTRitional Intervention among myeloproliferative Neoplasms): Feasibility Phase. medRxiv. doi:10.1101/2023.05.09.23289740

Data from Across Incyte’s Oncology Portfolio Accepted for Presentation at the 2023 ASCO Annual Meeting and EHA2023 Hybrid Congress

Posted on May 30, 2023May 30, 2023 by mpn_admin

May 25, 2023 05:01 PM Eastern Daylight Time

WILMINGTON, Del.–(BUSINESS WIRE)–Incyte (Nasdaq:INCY) today announced that multiple abstracts featuring data from across its oncology portfolio will be presented at the upcoming 2023 American Society of Clinical Oncology (ASCO) Annual Meeting held June 2-6 in Chicago, and at the European Hematology Association 2023 (EHA2023) Hybrid Congress held in Frankfurt, Germany, from June 8-11 and virtually from June 14-15.

“Our presence at ASCO and EHA illustrates Incyte’s ongoing commitment to science that can lead to additional, needed solutions for patients with cancer”

“Our presence at ASCO and EHA illustrates Incyte’s ongoing commitment to science that can lead to additional, needed solutions for patients with cancer,” said Steven Stein, M.D., Chief Medical Officer, Incyte. “These data underscore the potential of our oncology pipeline, and highlight the variety of approaches we are exploring to advance research in areas where we believe we can have the greatest impact for patients.”

Key abstracts accepted by ASCO and EHA include:

ASCO Abstracts

Abstracts are available to registered attendees on the ASCO Congress platform. Posters and slides will be available to registered attendees at the scheduled session start time.

Poster Discussion

LIMBER

Phase 1/2 Study of the Activin Receptor-Like Kinase (ALK)-2 Inhibitor Zilurgisertib (INCB000928, LIMBER-104) as Monotherapy or with Ruxolitinib (RUX) in Patients (pts) with Anemia due to Myelofibrosis (MF) (Abstract #7017. Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant. Monday, June 5, 12:30 p.m. – 2:00 p.m. ET)

Poster Presentations

CK0804

Phase 1b, Open-Label Study of Add-On Therapy with CK0804 in Participants with Myelofibrosis, with Suboptimal Response to Ruxolitinib (Abstract #TPS7087. Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant. Monday, June 5, 9:00 a.m. – 12:00 p.m. ET)¹

Immuno-oncology (IO)

A Phase 1/2 Study of Retifanlimab (INCMGA00012, Anti–PD-1), INCAGN02385 (Anti–LAG-3), and INCAGN02390 (Anti–TIM-3) Combination Therapy in Patients (Pts) with Advanced Solid Tumors (Abstract #2599. Session: Developmental Therapeutics—Immunotherapy. Saturday, June 3, 9:00 a.m. – 12:00 p.m. ET)

Itacitinib

Rates of Cytokine Release Syndrome (CRS) and Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS) from Center for International Blood and Marrow Transplant Research (CIBMTR) Data on U.S. Subjects (SUBJ) with Lymphoma Following Chimeric Antigen Receptor T Cell (CAR-T) Therapy (Abstract #7528. Session: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia. Monday, June 5, 9:00 a.m. – 12:00 p.m. ET)

LIMBER

Bromodomain and Extra-Terminal (BET) Inhibitor INCB057643 (LIMBER-103) in Patients (pts) with Relapsed or Refractory Myelofibrosis (R/R MF) and Other Advanced Myeloid Neoplasms: A Phase 1 Study (Abstract #7069. Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant. Monday, June 5, 9:00 a.m. – 12:00 p.m. ET)

EHA Abstracts

Abstracts are available on the EHA2023 Congress platform and accessible for on-demand viewing until August 15, 2023.

Oral Presentations

Ponatinib

PhALLCON: A Phase 3 Study Comparing Ponatinib vs Imatinib in Newly Diagnosed Ph+ALL (Abstract #S110. Session: Immune Therapeutic Treatment in ALL. Friday, June 9, Date, 8:45 a.m. – 9:00 a.m. ET)²

Ruxolitinib

Ruxolitinib in Pediatric Patients with Treatment-Naive or Steroid Refractory Chronic Graft-Versus-Host Disease: Primary Findings from the Phase 2 REACH 5 Study (Abstract #S245. Session: SCT Clinical. Saturday, June 10, 5:30 a.m. – 6:45 a.m. ET)³

Poster Presentations

LIMBER

Bromodomain and Extra-Terminal (BET) Inhibitor INCB057643 in Patients (pts) with Relapsed or Refractory Myelofibrosis (R/R-MF) and Other Advanced Myeloid Neoplasms: A Phase 1 Study (Abstract #P1055. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Phase 1/2 Study of the Activin Receptor-like Kinase 2 (ALK2) Inhibitor Zilurgisertib (INCB000928, LIMBER-104) as Monotherapy or with Ruxolitinib in Patients with Anemia due to Myelofibrosis (Abstract #P1022. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Parsaclisib

A Phase 2, Multicenter, Single-Arm Study of Parsaclisib, a PI3Kδ Inhibitor, in Relapsed or Refractory Follicular Lymphoma in China: Updated Results from the Study (Abstract #P1099. Session: Indolent and Mantle-Cell Non-Hodgkin Lymphoma – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)⁴

Ponatinib

Multicenter, Prospective and Retrospective Observational Cohort Study of Ponatinib in Patients with CML in Italy: Long-Term Follow-Up Results of the OITI Trial (Abstract #P663. Session: Chronic Myeloid Leukemia – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Early Cytogenetic or Molecular Landmark Response to Ponatinib Treatment Predicts Outcomes in Heavily Pretreated Patients with Chronic-Phase Chronic Myeloid Leukemia in PACE: 5-Year Data (Abstract #P670. Session: Chronic Myeloid Leukemia – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)³

Post Hoc Analysis of Patient Responses by T315I Mutation Status from the 3-Year Update of the OPTIC Trial: A Dose-Optimization Study of Three Starting Doses of Ponatinib (Abstract #P662. Session: Chronic Myeloid Leukemia – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)³

Ruxolitinib

Characteristics and Clinical Outcomes in Patients (Pts) With Polycythemia Vera (PV) Receiving Ruxolitinib (RUX) after Hydroxyurea (HU): A Longitudinal Analysis from REVEAL (Abstract #P1032. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Disease Progression and Leukemic Transformation in Patients with Lower-Risk Myelofibrosis (MF): An Analysis from MOST (Abstract #P1045. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Treatment Comparison of Hydroxyurea vs Ruxolitinib in Essential Thrombocythemia (ET): A Matched Cohort Analysis (Abstract #P1046. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Tafasitamab

Comprehensive Molecular Subtyping of Diffuse Large B-Cell Lymphoma Cell Lines and Association with Tafasitamab Activity (Abstract #P1227. Session: Lymphoma Biology & Translational Research. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Five-Year Efficacy and Safety of Tafasitamab in Patients with Relapsed or Refractory DLBCL: Final Results from the Phase 2 L-MIND Study (Abstract #P1138. Session: Aggressive Non-Hodgkin Lymphoma – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)⁵

For full session details and data presentation listings, please see the ASCO (https://conferences.asco.org) and EHA2023 (https://ehaweb.org/congress) online programs.

About Jakafi^® (ruxolitinib)
Jakafi^® (ruxolitinib) is a JAK1/JAK2 inhibitor approved by the U.S. FDA for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea; intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults; steroid-refractory acute GVHD in adult and pediatric patients 12 years and older; and chronic GVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi^® (ruxolitinib) outside the United States. Jakafi is a registered trademark of Incyte Corporation. Jakavi is a registered trademark of Novartis AG in countries outside the United States.

About Iclusig^® (ponatinib) tablets
Ponatinib (Iclusig^®) targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

In the EU, Iclusig is approved for the treatment of adult patients with chronic phase, accelerated phase or blast phase chronic myeloid leukemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation, or the treatment of adult patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.

Click here to view the Iclusig EU Summary of Medicinal Product Characteristics.

Incyte has an exclusive license from Takeda Pharmaceuticals International AG to commercialize ponatinib in the European Union and 29 other countries, including Switzerland, UK, Norway, Turkey, Israel and Russia. Iclusig is marketed in the U.S. by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

About Tafasitamab (Monjuvi^® / Minjuvi^®)
Tafasitamab is a humanized Fc-modified CD19 targeting immunotherapy. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb^® engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

In the United States, Monjuvi^® (tafasitamab-cxix) is approved by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In Europe, Minjuvi^® (tafasitamab) received conditional marketing authorization in combination with lenalidomide, followed by Minjuvi^® monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in several ongoing combination trials.

Monjuvi^® and Minjuvi^® are registered trademarks of MorphoSys AG. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name MONJUVI^® in the U.S., and marketed by Incyte under the brand name Minjuvi^® in Europe and Canada.

XmAb^® is a registered trademark of Xencor, Inc.

About Zynyz™ (retifanlimab-dlwr)
Zynyz (retifanlimab-dlwr), is an intravenous PD-1 inhibitor indicated in the U.S. for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Zynyz is marketed by Incyte in the U.S. In 2017, Incyte entered into an exclusive collaboration and license agreement with MacroGenics, Inc. for global rights to retifanlimab.

Zynyz is a trademark of Incyte.

About LIMBER
Incyte is a leader in the discovery and development of therapies for patients with myeloproliferative neoplasms (MPNs) and graft-versus-host disease (GVHD). The LIMBER clinical trial program is designed to evaluate multiple monotherapy and combination strategies to improve and expand treatments for patients with MPNs and GVHD. These include ruxolitinib-based combinations with BET and ALK2, new therapeutic options including axatilimab and novel targets such as mutant CALR.

New Risk Score Assists in Predicting Myeloid Neoplasms in Individuals With Clonal Hematopoiesis

Posted on May 30, 2023May 30, 2023 by mpn_admin

May 25, 2023

Vicki Moore, PhD

Researchers developed a clonal hematopoiesis risk score (CHRS) for patients with clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), and they evaluated its capacity to predict myeloid neoplasm (MN) risk in a recent study. Results were presented in the journal NEJM Evidence.

The study investigators obtained data from 438,890 individuals without MN who participated in the UK Biobank. Data on genetic mutations, laboratory values, and MN outcomes from 193,743 individuals were included in a subset used for derivation of the prognostic model, with the remaining 245,147 individuals included in a validation cohort. The primary study outcome was incident MN occurring after month 6 of study enrollment.

A total of 11,337 individuals in the derivation cohort were identified as meeting criteria for having either CHIP (10,479 individuals) or CCUS (858 individuals). The median follow-up duration was 11.7 years. In this cohort, there were 269 incident MN events reported, reflecting a rate of 2.37% in this population.

Several factors appeared associated with MN risk. These included high-risk mutations, single DNMT3A mutations, having 2 or more mutations, an age of 65 or more years, the presence of CCUS rather than CHIP, a mean corpuscular volume 100 fL or more, a red cell distribution width of 15% or more, and a variant allele fraction of 0.2 or more for any clonal hematopoiesis variant. Most of these features were linked to greater MN risk.

DNMT3A mutations were associated with a greater MN risk in individuals with CHIP/CCUS than in people without CHIP/CCUS. However, among individuals with CHIP/CCUS, DNMT3A mutations were associated with a lower risk of MN in comparison with other genotypes.

Using CHRS values developed with the prognostic model, the researchers categorized individuals with CHIP/CCUS into 3 risk groups. A low-risk group included 10,018 (88.4%) individuals, while an intermediate-risk group included 1196 (10.5%), and a high-risk group included 123 (1.1%).

In these groups, the 10-year cumulative incidence of MN was 0.669 ⁺ 0.0827% for the low-risk group, 7.83 ⁺ 0.807% for the intermediate-risk group, and 52.2 ⁺ 4.96% for the high-risk group. Ten-year survival rates were 93.7 ⁺ 0.243%, 84.0 ⁺ 1.06%, and 51.2 ⁺ 4.51%, respectively. In comparison, individuals without CHIP/CCUS in this study had a 10-year survival rate of 95.8 ⁺ 0.0471%.

“The CHRS robustly defines three distinct CHIP/CCUS risk groups and shows the low absolute risk of progression to overt MN in the vast majority of CHIP and CCUS,” the study investigators wrote in their report. They also concluded the CHRS may have a role in identifying individuals with CHIP/CCUS who may require greater surveillance and intervention.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Feasibility Phase

Posted on May 30, 2023May 30, 2023 by mpn_admin

Laura F. Mendez Luque,^1,² Julio Avelar-Barragan,³ Hellen Nguyen,¹ Jenny Nguyen,¹ Eli M. Soyfer,¹ Jiarui Liu,¹ Jane H. Chen,¹ Nitya Mehrotra,¹ Heidi E. Kosiorek,⁴ Amylou Dueck,⁴ Alexander Himstead,¹ Elena Heide,¹ Melinda Lem,¹ Kenza El Alaoui,¹ Eduard Mas Marin,¹ Robyn M. Scherber,⁵ Ruben A. Mesa,⁶ Katrine L. Whiteson,³ Andrew Odegaard,¹ and Angela G. Fleischman¹

Abstract

Purpose:

Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients.

Experimental Design:

We randomly assigned participants to either a Mediterranean diet or standard US Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four time points during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome.

Results:

The Mediterranean diet was as easy to follow for MPN patients as the standard USDA diet. Over 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any time point. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention.

Conclusions:

With dietician counseling and written education MPN patients can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially even be incorporated into the management of other chronic clonal hematologic conditions.

BET Inhibition Highlights Exploration of Novel Targeted Approaches in Myelofibrosis

Posted on May 30, 2023May 30, 2023 by mpn_admin

May 26, 2023

Ryan Scott

Andrew T. Kuykendall, MD, expands on the rationale for exploring BET inhibition in the treatment of patients with myelofibrosis, details the implications of data from the MANIFEST trial, and discusses other potential targets for novel therapies for myelofibrosis.

Although JAK inhibitors have been a standard of care for patients with myelofibrosis, the exploration of other targeted therapies such as BET inhibitors could lead to new agents and combinations to address symptoms for these patients, according to Andrew T. Kuykendall, MD, who added that disease modification remains a goal in the development of novel treatment approaches.

In the phase 2 MANIFEST trial (NCT02158858), 68% (95% CI, 57%-78%) of patients with JAK inhibitor–naïve myelofibrosis (n = 84) experienced a reduction in spleen volume of at least 35% (SVR35) at week 24 when treated with the combination of the BET inhibitor pelabresib (CPI-0610) and ruxolitinib (Jakafi). Additionally, 20% of patients with myelofibrosis who had previously experienced a suboptimal response to ruxolitinib (n = 81) experienced SVR35 at week 24.¹

Pelabresib plus ruxolitinib is being compared with ruxolitinib plus placebo in the phase 3 MANIFEST-2 trial (NCT04603495) in patients with JAK inhibitor–naïve myelofibrosis, and topline findings are anticipated by the end of 2023.²

“We need to do more [for patients with myelofibrosis] than what we’re currently doing. We see the limitations with single-agent JAK inhibition when we start to look at long-term data. It’s very effective and can change the lives of patients, but it seems to have a shelf life.” Kuykendall explained.

In an interview with OncLive^®, Kuykendall expanded on the rationale for exploring BET inhibition in the treatment of patients with myelofibrosis, detailed the implications of data from MANIFEST, and discussed other potential targets for novel therapies for myelofibrosis. Kuykendall is assistant member of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

OncLive: What makes BET inhibition a potentially valuable approach in myelofibrosis?

Kuykendall: BET inhibition has been looked at for a long time in many different circumstances, and it is an intriguing pathway specifically within the hematology space. One of the things that BET inhibition does is target the NF-κB inflammatory pathway and signaling pathway.

Recently, the focus in myelofibrosis and myeloproliferative neoplasms [MPNs] has been on the JAK-STAT pathway, which is the hallmark of the disease. All these driver mutations lead to JAK-STAT upregulation. However, this is an inflammatory disease, and it’s not just driven by 1 pathway. This isn’t a one-lane road that goes from one place to another. There are a lot of different pathways that are activated, and if you shut down that [road], [the disease is] going to find other roads around it, especially with the molecularly complex diseases and myelofibrosis, as opposed to essential thrombocythemia and polycythemia vera.

Patients come off JAK inhibitors, often by 3 years. They develop cytopenias and have symptoms that aren’t necessarily responsive to the JAK inhibitors, and they continue to have fatigue. With JAK inhibitors, we’re not seeing complete responses or partial responses. We are seeing very good but symptomatic improvement. The idea is that we may need to target multiple pathways of inflammation to be able to suppress the advantage this malignant clone has. We have great basic science that shows that the combination of BET inhibition and JAK inhibition is synergistic, or at least additive, from the clinical side of things to suppress this clone.

What has been the impact of the MANIFEST trial?

In the MANIFEST trial, we saw that when you treat with a BET inhibitor, it gives this additional level of benefit in terms of spleen volume control, symptom control, and maybe even anemia control. NF-κB may be more important in the cytopenia pathways.

There are emerging data when we look at some of the translational studies being done on the MANIFEST study that [suggest] maybe we are having some impact at the level of the bone marrow microenvironment, and maybe we are seeing some changes with these malignant megakaryocytes that seem to be the driving force behind this disease.

We need long-term data, and we need changes over time. The idea is that we’re bringing something additional to the table that not only can improve symptomatic responses, but maybe can lead to disease modification. We are suppressing enough of those inflammatory pathways that promote continued progression of these diseases, and we may be tipping the scales back in our favor.

Are there any targets beyond BET that have garnered further attention?

There are other targets that are certainly intriguing. The most intriguing one right now, other than BET, is the BCL-2/BCL-XL pathway. BCL-2 inhibitors with venetoclax [Venclexta] have gained a lot of traction in many different diseases, recently getting into the myeloid space with myelodysplastic syndromes and acute myeloid leukemia. However, maybe BCL-2 itself isn’t the key target in MPNs. It seems like BCL-XL might be more of the key target, [and that] is where navitoclax [(ABT-263) is directed]. [Navitoclax] is an older drug that wasn’t as effective or had some toxicity concerns in other diseases, and it is now being re-leveraged in [myelofibrosis] with good impact.

In the phase 2 [REFINE] study [NCT03222609], we saw that adding navitoclax to ruxolitinib was able to recapture spleen responses [with 27% of patients achieving a SVR35 at week 24 (n = 9/34)], which is not a small number.3 This [combination] has some mechanistic rationale and some clinical data to support it. [Navitoclax] is probably the most exciting targeted agent, besides what’s going on with BET inhibition.

We are looking at how to best target the NF-κB pathway. There are a lot of NF-κB inhibitors out there, and there is some interest right now in selinexor [Xpovio] as an XPO1 inhibitor. Selinexor certainly has gotten great responses in early phase studies. [Although] this [has been] in a small number of patients, it is exciting.

There are other targets and other pathways that we’re trying to figure out how to leverage. Myelofibrosis is an inflammatory disease, and that inflammation leads to continued disease progression and evolution of the disease. If we can figure out the most optimal way—which is probably not a one-size-fits-all situation—to stop that inflammation and suppress disease progression, there is potential for combination strategies.

What are your thoughts on combining agents up-front vs sequencing them?

Regarding the idea of combination strategies up-front vs add-ons, this is something that we’re not too sure about. If you can make the case that combination does not allow the disease to progress, then let’s leverage these [combinations] early on. However, you have to build that rationale.

On the contrary, if we’re just giving an extra level of symptomatic benefit and that’s what we’re shooting for, then start with a ruxolitinib- or JAK inhibitor–based therapy. If that works well and the patient feels well, continue with just that. If that doesn’t work effectively, if it is suboptimal, or you think [a patient] could do better, then add the other agent on and see what you can capture.

The idea for combination therapy is a push for disease modification. We hem and haw about what that actually means, but if we do think the disease is driven by multiple pathways of inflammation, then we need to hit it hard early with a combination strategy. However, to have that translate into clinical practice, you need good data to support that [disease modification is occurring].

Although many of these agents are still in early development, could targeted approaches potentially displace the role of stem cell transplant down the road?

It’s tough because none of these [agents] look like they’re curative at this point. If we can get meaningful, more durable, longer responses, then [targeted agents] could potentially replace transplant for a subset of patients. Right now, a lot of patients are diagnosed [at] older [ages], and with our limited treatment options, we’re considering transplant in a lot [of patients]. The equation is different if we can get sustained responses.

[For example, if you have] a 74-year-old patient with high-risk disease who you do not think is going to do well with the single-agent ruxolitinib approach and who is motivated for transplant, that changes the equation for that patient. Maybe with a combination or the potential to add something later on as ruxolitinib or the JAK inhibitor stops having as marked of an effect, that patient may decide to change course and pursue a different option and get good quality-of-life.

We know that transplant, while potentially curative, is not 100% [effective]. Even in patients who do get cured, it doesn’t mean that they have no toxicity from the transplant process. Often, patients come out on the other side a different person. While [targeted agents] won’t replace transplant, they could certainly obviate the need for transplant in a subset of patients.

What has exploration of different targeted approaches meant for the treatment landscape in myelofibrosis?

There are a lot of different agents at play, and there’s a ton of optimism. The overarching message is that we’re taking what we’re learning from the basic scientists and the translational scientists, and we’re putting that into rationally designed treatment options, we’re bringing that to patients, and we’re hopefully going to get new drug approvals.

We need to continue to understand that this is not going to be a one-size-fits-all approach. Navitoclax, pelabresib, selinexor, and any of these additional agents that go into late-stage development are not going to be great for every single [patient with] myelofibrosis. Right now, they’re being tested broadly in myelofibrosis. However, we need to work in the academic side to try to figure out which patients these [agents] benefit. Instead of giving [a treatment] broadly and getting a 30% response rate, let’s enrich the population with who’s likely to benefit, figure out how to get the right population, and get a 70% response rate.

There are toxicities to these additional agents. Especially when you treat with 2 agents over 1, you’re going to have multiple toxicities. Understanding who’s unlikely to benefit vs who’s likely to benefit can make a huge difference for patients clinically.

We do have to have some humility in this as well. We always reference the COMFORT studies [of ruxolitinib] and the JAKARTA studies of fedratinib [Inrebic] as far as our response rates and symptoms. However, I don’t believe that’s going to be how it plays out in phase 3 trials. We’re better now at patient selection, and patients who go on trials are typically more favorable than they were when we didn’t have any agents. We were putting anyone onto the COMFORT studies. [With improved patient selection], the response rates for the [control] arm [in future phase 3 trials] may be higher than we think, and that may present a challenge for getting some of these new agents approved because it is a higher bar to reach if you have to show significant improvement over a higher response [in the control arm].

These are exciting times. We’re going to get readouts of some of these big trials over the course of the next [couple] years. Hopefully, we have some new agents to leverage, but once we get the approvals, that is when we must do the real work and try to figure out how best to use these in practice.

References

Mascarenhas J, Kremyanskaya M, Patriarca A, et al. BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis – JAK inhibitor-naïve or with suboptimal response to ruxolitinib – preliminary data from the MANIFEST study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S198.
MorphoSys completes enrollment of phase 3 MANIFEST-2 study of pelabresib in myelofibrosis with topline results expected by end of 2023. News release. MorphoSys AG. April 4, 2023. Accessed May 23, 2023. https://www.morphosys.com/en/news/
Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy. J Clin Oncol. 2022;40(15):1671-1680. doi:10.1200/JCO.21.02188

Besremi Designated as Preferred Treatment for Polycythemia Vera

Posted on May 30, 2023May 30, 2023 by mpn_admin

Published on: May 26, 2023

Alex Biese

Two years after receiving FDA approval, Besremi is a preferred treatment option in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.

Besremi (ropeginterferon alfa-2b-njft) — a treatment for adults with the myeloproliferative neoplasm polycythemia vera (PV) — is now a preferred therapeutic option for patients with both high- and low-risk PV, regardless of their treatment history, according to the updated National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, according to a news release from drug developer, PharmaEssentia USA.

The U.S. Food and Drug Administration (FDA) approved Besremi in 2021, and last year the NCCN Guidelines were revised to include it as a recommended treatment for adults with PV, a type of blood cancer where the bone marrow makes too many red blood cells.

“Importantly, the NCCN Guidelines update includes moving Besremi to preferred status, reinforcing to treating physicians and patients that with its broad utility, Besremi is recommended for proactively treating PV,” Dr. John Mascarenhas, professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, said in the news release.

Besremi, as of the May 19 NCCN Guidelines update, is considered both a preferred treatment and a category 2A therapy, meaning “there is uniform NCCN consensus that the intervention is appropriate,” according to the PharmaEssentia announcement. It is currently intended to be administered every two weeks, or every four weeks after at least a year of hematological stability.

“This recent update to treatment guidelines by NCCN represents the community’s recognition of the value of Besremi as a therapeutic option for all adults with PV, regardless of their treatment history,” said Dr. Raymond Urbanski, head of clinical development and medical affairs for PharmaEssenta, in the press release. “Given its deep, durable control over the disease beyond the symptoms, we’re continuing to study Besremi in PV, as well as other myeloproliferative neoplasms (MPNs) and hematologic malignancies.”

The first patient was recently dosed in a 24-week phase 3B clinical trial evaluating an accelerated dose of Besremi — starting at 250 mcg then increasing to 350 mcg at week two, with a goal of 500 mcg at week four, as opposed to the currently approved dosing of 50 or 100 mcg. The study is expected to be completed in December 2025.