Pelabresib Combo Improves Spleen/Symptom Burden in JAKi-Naïve Myelofibrosis

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July 9, 2023

Russ Conroy

Combination treatment with pelabresib (CPI-0610) and ruxolitinib (Jakafi) was well tolerated and demonstrated enduring improvements in spleen and symptom burden among patients with JAK inhibitor treatment–naïve patients with myelofibrosis, according to findings from arm 3 of the phase 2 MANIFEST study (NCT02158858).

At week 24, 68% (95% CI, 57%-78%) of patients who received the combination achieved a spleen volume reduction of at least 35% (SVR35), which included a median SVR of –50% (range, –84% to 28%). Additionally, SVR35 responses at 24 weeks were observed in 70% and 67% of patients with intermediate-1– and intermediate-2– or high-risk disease based on Dynamic International Prognostic Scoring System (DIPSS) criteria, respectively, and 82% and 66% of patients based on International Prognostic Scoring System (IPSS) criteria. Kaplan-Meier estimates indicated that 93.5% (95% CI, 87.4%-99.7%) of those with a SVR35 response maintained their response at 36 weeks after onset.

A total symptom score reduction of at least 50% (TSS50) was reported in 56% (95% CI, 45%-67%) of patients at week 24, with a best TSS50 response at any time of 83% and a median change in TSS of –59% (range, –100% to 225%). Additionally, 43% of patients had a TSS50 response at 48 weeks, which included a median change in TSS of –54.8% (range, –100% to 307.1%).

At 24 weeks, study treatment yielded an absolute change in hemoglobin levels from baseline between –1 and at least 1.5 g/dL in 55% of patients; hemoglobin levels improved in 36% of patients, including a mean change of 1.3 g/dL and a median of 0.8 g/dL. Moreover, 24% of patients had a mean hemoglobin increase of at least 1.5 g/dL from baseline over any 12-week period while forgoing red blood cell transfusions.

“To our knowledge, the MANIFEST trial in JAK inhibitor treatment-naïve patients is the first study with a rational combination of BET [inhibitor] pelabresib and ruxolitinib that showed clinically meaningful durable improvements in splenomegaly and symptoms, was associated with biomarker findings indicating potential disease modification, and demonstrated a generally favorable safety profile,” the study authors stated. “This combination has the potential to improve the standard of care for treatment-naïve patients with myelofibrosis and warrants further investigation.”

Investigators of the global, open-label, nonrandomized phase 2 MANIFEST study evaluated pelabresib in combination with ruxolitinib in a cohort of JAK inhibitor treatment-naïve patients with myelofibrosis. Patients received an initial dose of 125 mg of pelabresib once daily for 14 days followed by a 7-day pause in combination with continuous ruxolitinib twice a day. Patients could receive a maximum pelabresib dose of 175 mg once daily.

The study’s primary end point was SVR35 from baseline to 24 weeks measured by imaging. The secondary end point was TSS50, and exploratory end points included bone marrow fibrosis improvement based on blinded central hematopathologist review following European consensus guideline criteria for reticulin fibrosis grading and improvement in anemia and transfusion requirements.

Patients who had not been exposed to treatment with JAK inhibitors and BET inhibitors and had confirmed diagnoses of primary myelofibrosis, or post–essential thrombocythemia or post–polycythemia vera myelofibrosis were eligible for enrollment on the trial. Additional eligibility criteria included having a spleen volume of at least 450 cm3, intermediate-2– or high-risk disease based on DIPSS criteria, and at least 2 measurable symptoms using the Myelofibrosis Symptom Assessment Form v4.0.

Overall, 84 patients received at least 1 dose of the study treatment, 53 of whom remained on treatment at the time of data cutoff. The median patient age was 68 years (range, 37-85), and 70% were male. Additionally, 24% had intermediate-1, 61% had intermediate-2, and 16% had high-risk disease by DIPSS criteria. In terms of mutations, investigators most frequently observed JAK2V617F (74%), ASXL1 (46%), CALR (21%), and MPL (8%).

Blinded central pathology review of bone marrow samples indicated at least 1 grade improvement in reticulin fibrosis at week 24 in 28% of evaluable patients, including 7% who had improvements of 2 grades. Among 24 patients with grade 1 or 2 reticulin fibrosis at baseline, 4 had worsening conditions, including 2 patients each with grade 1 and 2 fibrosis. Investigators observed no significant relationship between reticulin fibrosis improvement and clinical end points in the study,

Overall, 96% of patients experienced at least 1 treatment-emergent adverse effect (TEAE), and 63% had grade 3 or higher TEAEs. The most frequent hematologic TEAEs included thrombocytopenia (52%) and anemia (42%), and the most common nonhematologic TEAEs included diarrhea (35%), fatigue (33%), musculoskeletal pain (30%), respiratory tract infection (29%), and constipation (25%).

Pelabresib dose reductions were necessary among 37% of patients, and 36% had ruxolitinib dose reductions due to TEAEs. There were 5 deaths during study treatment or within 30 days following the final pelabresib dose, including 4 determined to be unrelated to pelabresib treatment. One patient died to multiorgan failure due to sepsis secondary to pneumonia, which investigators deemed to be related to pelabresib.

Reference

Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol. Published online March 7, 2023. doi:10.1200/JCO.22.01972

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Examining Pelabresib for Patients With Myelofibrosis

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July 9, 2023

Joseph Scandura, MD, PhD

Joseph M. Scandura, MD, PhD, Weill Cornell Medicine, discusses next steps for research of pelabresib (CPI-0610) for use in patients with myeloproliferative neoplasms.

Pelabresib is an oral, small molecule inhibitor of BET, which has the potential to downregulate the expression of genes that reside within the pathogenic pathways that underlie MPN progression.

One study evaluating pelabresib is the phase 3 MANIFEST-2 trial (NCT04603495). In this multicenter, double-blind, placebo-controlled trial, investigators are examining the safety and efficacy of pelabresib plus ruxolitinib (Jakafi) vs ruxolitinib alone in patients with JAK inhibitor-naïve myelofibrosis.

Patients aged 18 years and older with primary, post-polycythemia vera, or post-essential thrombocytopenia myelofibrosis, who had advanced disease requiring therapy, splenomegaly by computed tomography or magnetic resonance imaging, and were symptomatic were eligible for enrollment. Patients must also have had a prognostic risk-factor score of intermediate-1 or higher per the Dynamic International Prognostic Scoring System.

In the study, patients were randomly assigned in a 1:1 ratio to receive ruxolitinib in addition to oral pelabresib or matched placebo daily for 14 days, which was followed by 7 days off treatment. The starting dose of pelabresib was 125 mg daily. Then, ruxolitinib was given to patients twice a day in doses of 10 mg or 15 mg. Dose increases for both were allowed per protocol criteria.

Transcription:

0:10 | The first one is that we need to wait for the data to mature. My personal bias is, all of these biomarkers are invaluable until we know outcomes such as survival or time to treatment failure or event-free survival. Until we know that, we are just kind of stuck in this circular loop of what should be, what we hope will be, what our intuitive beliefs are, but we do not really know what any of these things mean until we have those outcomes. That just takes time.

0:46 | The nice thing is there are a number of phase 3 studies, randomized trials, collaborative studies. MANIFEST-2 is a randomized phase 3 study, and that will allow us to address and follow up on some of these findings, and hopefully get to those answers about whether or not these changes that we’re observing in the short-term are predicting these long-term beneficial outcomes. It just takes time for that data to mature

REFERENCE
Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated April 6, 2023. Accessed July 6, 2023. https://clinicaltrials.gov/ct2/show/NCT04603495

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Navtemadlin With Ruxolitinib Leads to SVR Benefit in TP53 Wild-Type Myelofibrosis

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July 7, 2023

Kyle Doherty

The addition of the MDM2 inhibitor navtemadlin (formerly KRT-232) to ruxolitinib (Jakafi) led to clinically meaningful improvements in spleen volume reduction (SVR) among patients with primary or secondary TP53 wild-type myelofibrosis who had a suboptimal response to ruxolitinib, according to findings from the phase 1/2 KRT-232-109 study (NCT04485260) presented during the 2023 European Hematology Association (EHA) Congress.

Results from the trial showed that at 24 weeks among efficacy-evaluable patients (n = 19) adding navtemadlin to ruxolitinib conferred a minimum SVR of 25% in 42% of patients and an SVR of at least 35% in 32%. Additionally, a minimum total symptom score (TSS) improvement of at least 50% was observed in 32% of patients.

“This therapeutic approach is clearly active,” John O. Mascarenhas, MD, said. “The combination of navtemadlin and ruxolitinib achieves two things: synergy in terms of cell kill directed at the CD34 myeloblasts population, which is really what we’re trying to accomplish, and an improved toxicity profile [compared with] monotherapy. This is a combination that could potentially even be used upfront in the JAL inhibitor-naïve patient population. MDM2 inhibition is here and likely is going to be a component in the future. Navtemadlin is poised to be at the forefront as a first-in-class agent to deliver that kind of clinical activity.”

In an interview with OncLive®, Mascarenhas, professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of Tisch Cancer Institute in New York, New York, discussed the design and rationale of KRT-232-109, more key findings from the trial, and potential future directions of the study.

OncLive: What is the mechanism of action of navtemadlin and what was the rationale for evaluating it in KRT-232-109?

Mascarenhas: Myelofibrosis is predominantly a TP53 wild-type disease. MDM2 negatively regulates TP53. [The] p53 pathway is important for regulating cell fate and balancing prosurvival and prodeath signals.

In myelofibrosis, MDM2 is overexpressed in CD34 cells, and this negatively regulates TP53 activity. It’s an alternative mechanism for cancer cells to increase the threshold for induction of apoptosis. Navtemadlin interrupts that interaction between MDM2 and wild-type TP53, thereby activating TP53 and inducing apoptosis.

What’s exciting about the phase 1b/2 study adding navtemadlin to patients receiving ruxolitinib with a suboptimal response is [the fact that] ruxolitinib works synergistically with navtemadlin in reducing p21. [This] essentially lowers the threshold to induce apoptosis in the setting of navtemadlin, so the two work well together to induce apoptosis in myelofibrosis CD34 cells—there’s great preclinical data that justify this concept.

What were the goals of the KRT-232-109 study?

The goal of the phase 1 was to determine the recommended phase 2 dose of navtemadlin in combination with ruxolitinib in these suboptimal ruxolitinib-[responding] myelofibrosis patients.

We evaluated 3 different dose levels and different dose schedules, and the recommended phase 2 dose based [not only] on the clinical results, but also on some of the pharmacokinetic results that were that were conducted is 240 mg of navtemadlin 7 days in a row of a 28-day cycle. [It’s a] 1-week-on-3-week-off [schedule of] 1-month cycles with the stable dose of ruxolitinib that the patient is on. So, you don’t adjust the dose of ruxolitinib, you simply add navtemadlin.

The ongoing purpose of the phase 2 [study] is to document the efficacy as measured by SVR and symptom improvement at 24 weeks.

What were some of the key inclusion criteria?

Patients had to have a platelet count greater than 100,000 because we often use platelet counts in these trials to determine eligibility. Patients had to have TP53 wild-type disease. Importantly, this approach is probably not effective in patients who have mutant disease because MBM2 doesn’t regulate mutant TP53. [Patients also needed to be] on ruxolitinib for at least 18 weeks, which is the minimal amount of time needed to determine whether someone has an optimal [response], suboptimal [response], or progressive disease, and at a stable dose of ruxolitinib for 8 weeks.

What were the key efficacy findings from KRT-232-109 presented during the 2023 EHA Congress?

We looked [what] we would normally look at in myelofibrosis, [such as] spleen response. The SVR [of] at least 35% at 24 weeks in evaluable patients was 32%. If you look at SVR [of at least] 25%, which is also considered by regulatory agencies a meaningful spleen response at 24 weeks, it was 42%. There was clear spleen reduction, and most patients [experienced] some degree of spleen response.

Symptom improvement was also seen; 32% of patients at week 24 had a 50% or greater TSS score and some of these patients had very significant spleen symptom burden at baseline. The drug was effective in addressing those 2 clinical end points.

What was really interesting was that patients, in some cases, had ruxolitinib doses of 5 mg twice daily going into the study, meaning they were coming in at low doses. And despite low doses of ruxolitinib, there was synergistic activity with navtemadlin[and] we were seeing very deep spleen and symptom responses. This speaks to the fact that biologically there is a priming almost of the diseased cells for TP53 induction of apoptosis with ruxolitinib. The preclinical data supported and translated very nicely into the clinical findings.

Are there any safety concerns clinicians should be aware of when using navtemadlin plus ruxolitinib?

[This was a] well-tolerated drug. We know that, as a class of agents, there is a degree of gastrointestinal [GI] toxicity with MDM2 inhibitors, [including] nausea, vomiting and diarrhea. [These events were] rarely grade 3/4 [in severity]; 70% of were grade 1. [Approximately] 60% of patients experienced some GI toxicity, usually in the first 2 cycles. Preemptively, we give antiemetic and an antidiarrheal. That is a very effective way of managing those nausea and diarrhea type toxicities.

The [inclusion] of ruxolitinib it seems to offset some of that toxicity. There may be some biologic reasons why there’s synergy with ruxolitinib, not just an efficacy, but also in improving the safety profile with navtemadlin. The deep responses that we see are also complemented by a well-tolerated combination.

What are the next steps for this research?

We want to finish the follow-up of patients enrolled in phase 2. We still have ongoing correlatives to look at. We presented correlatives that were very encouraging [showing] that we were having on-target stem cell–directed therapeutic effects, [such as] reduction of CD34 cell burden, reduction in bone marrow fibrosis, and reduction in driver RAF level in these patients that were treated.

We were clearly having disease-modifying effect, biologic response modification. We want to see that in a greater number of patients [and] I’d love to see some of the cytokine results. There’s still more to be done from a correlative science aspect and patient follow-up to be conducted.

Ultimately, where this will go is to a phase 3 study, which will be entitled BOREAS-2, where we’ll be [enrolling patients with] suboptimal ruxolitinib response and adding navtemadlin [and evaluating this treatment] vs placebo to improve responses.

Reference

Mascarenhas J, Jain T, Otoukesh S, et al. An open-label, global, phase (Ph) 1b/2 study adding navtemadlin (NVTM) to ruxolitinib (RUX) in patients (Pts) with primary or secondary myelofibrosis (MF) who have a suboptimal response to RUX. HemaSphere. 2023;7(suppl 3):S210.

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NCCN Guidelines Update Recommends Ropeginterferon Alfa-2b for Polycythemia Vera

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July 7, 2023

Rose McNulty

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology was recently updated to include ropeginterferon alfa-2b (Besremi; PharmaEssentia) as a preferred treatment option for patients with high- and low-risk polycythemia vera (PV), according to a press release from PharmaEssentia USA Corporation.1

The updated guidelines recommend ropeginterferon alfa-2b and designate the recommendation as category 2A, which signifies a uniform NCCN consensus that ropeginterferon alfa-2b is an appropriate intervention for patients with PV. The agent was granted FDA approval for the treatment of PV in 2021 and was the first FDA-approved treatment indicated for PV regardless of previous treatment.2

“Importantly, the NCCN Guidelines update includes moving [ropeginterferon alfa-2b] to preferred status, reinforcing to treating physicians and patients that with its broad utility, [ropeginterferon alfa-2b] is recommended for proactively treating PV,” said John Mascarenhas, MD, professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, in a statement.1

PV, a rare hematological malignancy and the most common chronic myeloproliferative neoplasm, is characterized by overproduction of red blood cells in bone marrow that can lead to elevated white blood cell and platelet counts. Ropeginterferon alfa-2b is a monopegylated, long-acting interferon that blocks the signals that cause malignant cells to multiply.

The FDA approval of ropeginterferon alfa-2b was based on safety data from the PEGINVERA (NCT01193699) trial; PROUD-PV (NCT01949805) and its open-label extension portion, CONTINUATION-PV (NCT02218047); and efficacy data from the PEGINVERA clinical study program, according to a press release following the 2021 approval.3

Efficacy results showed that 61% of patients experienced complete hematological response—defined as hematocrit less than 45% without phlebotomy for at least 2 months since the patient’s last phlebotomy, platelet counts of 400 x 109/L or less, leukocytes of 10 x 109/L or less, and normal spleen size—following 7.5 years of treatment with ropeginterferon alfa-2b. Based on objective laboratory parameters, 80% of patients achieved a hematological response in the study.

As far as safety, ropeginterferon alfa-2b was shown tolerable in a pooled safety population, with the most common adverse reactions with incidence of 40% or higher being influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain. Serious adverse reactions occurring in less than 4% of cases were urinary tract infection, transient ischemic attack, and depression.

New data from the PROUD-PV and CONTINUATION-PV studies were presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition last December, adding to evidence in support of ropeginterferon alfa-2b for PV. In one abstract, the majority of both low- and high-risk patients with PV (85.7% and 75.0%, respectively) in the CONTINUATION-PV trial did not require phlebotomy for the entire sixth year of treatment.4

“This recent update to treatment guidelines by NCCN represents the community’s recognition of the value of [ropeginterferon alfa-2b] as a therapeutic option for all adults with PV, regardless of their treatment history,” said Raymond Urbanski, MD, PhD, US. Head of Clinical Development and Medical Affairs at PharmEssentia. “Given its deep, durable control over the disease beyond the symptoms, we’re continuing to study [ropeginterferon alfa-2b] in PV, as well as other myeloproliferative neoplasms (MPNs) and hematologic malignancies.”

References

1. NCCN Clinical Practice Guidelines in Oncology updated to recommend Besremi (ropeginterferon alfa-2b-njft) as a preferred intervention for polycythemia vera. News release. PharmaEssentia USA Corporation. May 23, 2023. Accessed May 24, 2023. https://us.pharmaessentia.com/wp-content/uploads/2023/05/NCCN_Guidelines_Update_Press_Release_May-23-2023.pdf

2. FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed July 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-rare-blood-disease

3. US FDA approves Besremi (ropeginterferon alfa-2b-njft) as the only interferon for adults with polycythemia vera. News release. PharmaEssentia Corporation. November 12, 2021. Accessed July 6, 2023. https://us.pharmaessentia.com/wp-content/uploads/2021/11/BESREMi-FDA-Approval-November-12-2021.pdf

4. Caffrey M, Shaw ML, Klein H. ASH 2022: rare diseases & blood disorders. Am J Manag Care. 2023;29(SP1):SP42-SP46.

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Don’t Shy Away From Discussing MPN Side Effects

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July 6, 2023

Brielle Benyon

It is essential that patients being treated for a myeloproliferative neoplasm (MPN) be upfront with their clinicians about side effects that they experience, explained Julie Huynh-Lu, a physician assistant from The University of Texas MD Anderson Cancer Center in Houston.

MPNs neoplasms are a group of blood cancers that causes the bone marrow to produce too much red or white blood cells or platelets. While there are multiple treatments for MPNs depending on the patient’s characteristics and individual disease type, common side effects, according to Huynh-Lu, include diarrhea, frequent infections and pneumonia.

Patients may feel apprehensive about discussing side effects with their care team in fear of being taken off treatment. But they shouldn’t be, Huynh-Lu, explained.

“So sometimes it could be something as simple as putting a band-aid on it … let’s say they started treatment and they’re having worsening itching. Well, there’s medications that I can use to treat the worsening itching,” Huynh-Lu said in an interview with CURE®. “If the drug is controlling their disease, then let’s just put a band-aid on it and go from there. If they are having progression and disease, that’s something different.”

If a patient’s disease is getting worse on treatment, there are options, too, such as switching to a different type of treatment or enrolling in a clinical trial, Huynh-Lu said.

Transcription

My advice probably would be if you’re having these side effects, then the idea of being on treatment is to help you feel better, right? And not just prolonging your life and treating the disease — it’s to improve your quality of life. So if you’re having these symptoms, that honestly might be (worsening) your quality of life, then it certainly bodes having a conversation with your provider on whether or not the current treatment is the right one for you. Because there could be other options out there, and it’s worth exploring; it doesn’t mean necessarily that you have to jump ship and go straight to a different treatment, obviously, but it’s worth it to discuss with someone, what else is out there, because you might not know what else is out there for yourself.

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Phase 3 Trial of Selinexor and Ruxolitinib Starts in JAKi-Naive Myelofibrosis

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June 30, 2023

Jordyn Sava

A phase 3 clinical trial (NCT04562389) has been initiated to assess the efficacy and safety of selinexor (Xpovio) given once a week at 60 mg in combination with ruxolitinib (Jakafi) in JAK inhibitor (JAKi)-naïve patients with myelofibrosis, according to Karyopharm Therapeutics, Inc.1

The start of this phase 3 study is supported by phase 1 study results that showed rapid, deep, and sustained spleen responses and robust symptom improvement among patients at week 24 who were treated at the 60 mg dose level.

Findings revealed a 78.6% spleen volume response rate of ≥ 35% (SVR35) and 58.3% symptom improvement of ≥ 50% (TSS50) in the intent to treat patients, and SVR35 responses were observed in all 12 of the evaluable patients at any time. Additionally, rates were consistent regardless of subgroups, including patients treated with low dose ruxolitinib.

An improvement in major spleen and cytokine-related symptoms were observed and treatment with selinexor was generally well tolerated with a manageable adverse event (AE) profile. Most patients were able to remain on therapy for up to 74 weeks, and the most common treatment emergent AEs experienced with the 60 mg selinexor dose with ruxolitinib included nausea (78.6%), anemia (64.3%), thrombocytopenia (64.3%) and fatigue (57.1%).

The most common treatment-emergent grade ≥3 AEs with the combination with ruxolitinib were anemia (42.9%), thrombocytopenia (28.6%), and back pain (14.3%). Moreover, 75% of nausea events were grade 1 and did not lead to treatment-related discontinuations.

“The substantial degree of spleen volume reduction observed across all subgroups with selinexor 60 mg in combination with ruxolitinib is very encouraging. There is a significant unmet need in the treatment of patients with myelofibrosis, and these data demonstrate that the addition of XPO1 inhibition with selinexor with standard-of-care ruxolitinib has the potential to significantly improve outcomes for first-line myelofibrosis patients,” said John Mascarenhas, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Center of Excellence for Blood Cancers and Myeloid Disorders, in a press release. “As the principal investigator for the phase 3 study, I look forward to defining a potential new standard of care for JAK-naïve patients [with myelofibrosis].”

In the randomized, double-blind, placebo-controlled phase 3 study, approximately 306 JAKi-naive patients with intermediate or high-risk myelofibrosis will be enrolled and randomized in a 2:1 fashion to receive ruxolitinib plus selinexor 60 mg or ruxolitinib plus placebo in 28-day cycles.2

Enrollment in the study is open to patients aged 18 years and older with a diagnosis of primary myelofibrosis, post-essential thrombocythemia, or post polycythemia vera myelofibrosis who have a measurable splenomegaly during the screening period, an international prognostic scoring system risk category of intermediate-1, or intermediate-2, or high-risk, an ECOG performance status of less than or equal to 2, and a life expectancy of greater than 6 months. Additionally, patients must have active symptoms of myelofibrosis, and provide bone marrow biopsy samples at screening and during the study.

The coprimary end points of the study include SVR35 and TSS50 at week 24. The key secondary end point of the study is anemia response at week 24 with other secondary end points for the phase 3 portion including overall survival, overall response rate, pharmacokinetics, and number of patients with AEs.

The study is currently recruiting patients in Virginia and is active at sites in California, Tennessee, and Utah. The estimated study completion date is December 2027.

Top-line data are expected to read out from this phase 3 study in 2025, and the company plans to further investigate selinexor in other frontline opportunities, including in combinations for the treatment of myelofibrosis.1

“Selinexor and ruxolitinib appear to work synergistically, resulting in meaningful improvements in spleen response and total symptom score for patients with myelofibrosis,” said Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, in a press release. “We believe that an opportunity exists to expand upon the initial response, depth, and duration of JAK inhibitors to ultimately improve patient outcomes. This combination has the potential to become a cornerstone treatment in frontline myelofibrosis and we are excited to start this pivotal trial to deliver on our goal of bringing forward an innovative new approach for the treatment of myelofibrosis that can benefit [patients with myelofibrosis].”

REFERENCES:
  1. Karyopharm initiates pivotal phase 3 study of XPO1 inhibitor selinexor and ruxolitinib in JAK inhibitor (JAKi) naïve myelofibrosis. News release. Karyopharm Therapeutics, Inc. June 28, 2023. Accessed June 30, 2023. https://tinyurl.com/4phpud2y
  2. Study of selinexor in combination with ruxolitinib in myelofibrosis. ClinicalTrials.gov. Updated June 29, 2023. Accessed June 30, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04562389

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Lindsey Lyle on Differentiating MPN Symptoms From Other Health Issues

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June 30, 2023

Lindsay Lyle, PA-C, MS

It can often be difficult for oncology nurses and other clinicians to determine if a patient’s symptoms are related to their myeloproliferative neoplasm (MPN) or another underlying cause, making a detailed medical history extremely important, explained Lindsey Lyle, PA-C, MS, a nurse practitioner who specializes in hematologic malignancies.

“This is a big challenge for nurses, advanced practice providers and physicians alike,” Lyle said in an interview with Oncology Nursing News®.

Common MPN symptoms — including fatigue, bone aches and pains, night sweats, unintentional weight loss, rib pain and feeling full after eating small amounts of food — are relatively broad and can be associated with numerous health conditions, Lyle said, noting that it is important to rule out other possible causes.

To ensure that these symptoms are not related to another cause, nurses must ask patients about their past medical history, other health conditions, changes in medications, and timing of symptoms. Lyle noted that the patient’s primary care physician can also be a good source of information regarding the timing of a patient’s symptoms.

“When a patient does have a diagnosis of an MPN, we certainly can assume that maybe it is the MPN until other contributors have been ruled out,” Lyle said. “So timing of these symptoms is really important; a nurse can ask about when symptoms first started, what they were doing when these symptoms happened and what makes them better, or what makes them worse.”

Additionally, Lyle mentioned that nurses should ask patients about how treatments change their symptoms, as some drugs that are currently used to treat MPNs — such as the JAK inhibitors ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo) — can decrease symptoms, such as splenomegaly. In fact, last year, the Food and Drug Administration (FDA) approved pacritinib for patients with intermediate- or high-risk primary or secondary myelofibrosis because the phase III PERSIST-2 trial showed that the drug decreased spleen volume by at least 35% in 29% of patients.1

Reference

  1. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

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Validation of myeloproliferative neoplasms associated risk factor RDW as predictor of thromboembolic complications in healthy individuals: analysis on 6849 participants of the SHIP-study

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June 23, 2023

Kirsi Manz, Jeanette Bahr, Till Ittermann, Konstanze Döhner, Steffen Koschmieder, Tim H. Brümmendorf, Martin Griesshammer, Matthias Nauck, Henry Völzke & Florian H. Heidel

Chronic myeloproliferative neoplasms (MPN) are characterized by hyperproliferation of myeloid cells leading to erythrocytosis, thrombocytosis, leukocytosis and splenomegaly. Thromboembolic events (TE) are among the most prevalent complications in patients with different subtypes of MPN such as polycythemia vera (PV) [1, 2], with arterial and venous thromboses being among the major causes of morbidity and mortality. Pathophysiologic mechanisms that contribute to TE complications, besides increased cell counts, include functional alterations of leucocytes, red blood cells, platelets and endothelial cells [3]. The rate of thromboembolic complications in MPN patients ranges from 1.1 to 4.4% per year, while this rate is significantly lower in the normal population (0.6 and 0.9% per year in the absence or presence of cardiovascular risk factors, respectively) [4, 5]. Therefore, prediction of occurrence of thromboembolic events for risk estimation is of great importance. While the risk of these patients to experience thromboembolic complications is clearly high, prognostic parameters beyond age and past history of thrombosis are currently lacking. This leads to challenges in clinical decision making regarding the indication of cytoreductive drugs and the prophylaxis and use of anticoagulants. Therefore, in our previous work, we used a machine learning algorithm to identify risk factors for this high-risk population of patients with PV for clinical use that can predict thromboembolic events [6]. Using the publicly available OPTUM database that consists of patient data provided by US insurance companies, we could define red cell distribution width (RDW), lymphocyte and platelet counts as independent prognostic parameters for thromboembolic events: Lymphocyte ratio (LYP) and RDW predicted the risk of occurrence of TEs of patients without a history of TEs within the next 12 months. In addition, predictive factors for patients with a history of TE complications included lymphocyte ratio and platelet count. Recently, neutrophil-lymphocyte ratio (NLR) was confirmed as predictive risk factor for venous thrombosis in an independent retrospective cohort of PV patients [7]. While these analyses require prospective validation in clinical trials, the predictive value of these parameters in a normal control population without myeloproliferation or hematopoietic cancers remains to be investigated.

In order to validate these findings in a control cohort of non-MPN patients, we retrieved data of the SHIP study conducted at Greifswald University Medicine. The Study of Health in Pomerania (SHIP) is a population-based epidemiological study consisting of currently 5 independent cohorts [8]. The SHIP investigates common risk factors, subclinical disorders and manifest diseases with highly innovative non-invasive methods in the population of northeast Germany. As this study is not focused on one specific disease it aims to investigate health in all aspects and complexity involving the collection and assessment of data relevant to the prevalence and incidence of common, population-relevant diseases and their risk factors.

We utilized data from different independent cohorts of the SHIP study: the baseline examination of SHIP-START (SHIP-START-0) between 1997 and 2001 (n = 4308), and the baseline examination of SHIP-TREND (SHIP-TREND-0) between 2008 and 2011 (n = 4420). After excluding missing datapoints, a total of 2491 datasets (derived from individual participants) from the SHIP-START-0 and 4358 from the SHIP-TREND-0 were included in the analyses. Data on all probands with baseline data on RDW, lymphocyte percentage, platelet count, body mass index (BMI), prior TE, neutrophil percentage, leukocytes and hematocrit was used for the study. Also, all documented medication was recorded and included for analysis. Of note, SHIP-START-0 data does not include differential blood counts, including lymphocyte and neutrophil percentage. Occurrence of TE in SHIP-START was defined as thrombosis, stroke or myocardial infarction or use of an antithrombotic agent while SHIP-TREND also included evidence of thrombophlebitis. Antithrombotic agents were defined as agents belonging to the Anatomical Therapeutic Chemical (ATC) classification system section B01 “antithrombotic agents”. This section includes oral anticoagulants such as vitamin K antagonists, platelet inhibitors (ASA and P2Y-antagonists) and direct oral anticoagulants (DOACs) among others. Single use of antithrombotic agents e.g. for in-flight prophylaxis was not considered. Cardiovascular risk factors included were elevated blood lipids, hypertension, diabetes mellitus, current smoking, BMI, and subjects’ age. Subjects with missing diabetes mellitus status and HbA1c > = 6.5% were counted as diabetic. In the absence of elevated blood lipid status, subjects with cholesterol > = 6 mmol/l and/or triglyceride > 1.9 mmol/l were assigned to elevated blood lipids. Descriptive statistics are provided as median and minimum – maximum, or as frequency and percentage, as appropriate. The non-parametric Mann Whitney U test was used to assess differences of continuous variables between two groups. Categorical variables were compared using the Fisher’s exact test. First, all candidate variables were adjusted for age and sex. Then, all significant age- and sex-adjusted variables were included in the backward variable selection procedure. Variable selection was performed 1000 times using bootstrapping methods. To report the most relevant variables, the final model consists of those selected in at least 80% of the bootstrapping runs. In both cohorts, 70% of the data were used to build and 30% were used to validate the model. To assess the predictive value of both models, accuracy and receiver operating characteristic (ROC) curve were calculated. Statistical significance was claimed at 5% (p < 0.05) and no correction for multiple testing was performed. The data was prepared using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and analyzed using R Version 4.2.2 [9].

Regarding baseline characteristics, TE events had occurred in 321 (12.9%) of the 2491 individuals of the SHIP-START cohort while the prevalence of TE events was 21.4% (932 events in 4358 individuals) in the SHIP-TREND cohort. Overall, established risk factors for TE such as male sex, higher age, higher body-mass-index (BMI), arterial hypertension, hypercholesterolemia, and diabetes mellitus were associated with significantly higher rate of TE events (Table 1). Of note, TE events were more frequently reported in non-smokers compared to smokers in both cohorts. In regard to laboratory parameters, higher RDW and lower platelet counts showed significant association with TE complications. In contrast, higher leukocyte counts, lower hematocrit and lower lymphocyte ratio showed exclusively significance in the SHIP-TREND cohort analysis.

Table 1 Baseline characteristics of both cohorts.

To assess for effects of the above risk factors on TE events, we used multivariable logistic regression models. When investigating the SHIP-START cohort of 2491 individuals, male sex (p < 0.0001), presence of hypertension (p = 0.0042), hypercholesterolemia (p < 0.0001) or diabetes mellitus (p = 0.0008), and higher age (p < 0.0001) were validated as TE risk factors. Regarding laboratory parameters, higher RDW (p = 0.0006) was the only predictor for TE complications.

Analysis of the SHIP-TREND cohort of 4358 individuals confirmed independent predictive value of higher age (p < 0.0001) and hypercholesterolemia (p < 0.0001) while elevated body mass index (BMI; p = 0.0003) scored as an additional predictive factor due to availability of the respective data points in this cohort. In contrast, male sex and hypertension were not confirmed as independent risk factors. Consistent with the SHIP-START cohort, higher RDW (p < 0.0001) was identified as predictive for TE events, along with lower platelet counts (p < 0.0028). Taken together, alterations of laboratory parameters such as red cell distribution width and platelet count at study entry were associated with occurrence of thromboembolic events in this retrospective assessment of individuals without evidence for hematologic malignancies.

When adjusting for age and sex (Fig. 1A, B), BMI, hypercholesterolemia, hypertension, diabetes mellitus and RDW consistently showed elevated odds ratios in both cohorts, using the basic model. Assessment for TE risk factors in the final model confirmed age, hypercholesterolemia and RDW as predictors of thromboembolic events in both cohorts. Here, RDW showed an OR of 1.28 (95% CI: 1.11–1.47) for SHIP-START and 1.25 (95% CI 1.12–1.38) for SHIP TREND (Fig. 1C, D). Of note, the SHIP-TREND model could also be validated using SHIP-START data. In order to select an optimal model, receiver operating characteristic (ROC) analysis was performed showing an AUC of 0.846 (95% CI: 0.805–0.886) for SHIP-START and an AUC of 0.847 (95% CI: 0.827–0.866) for SHIP-TREND (Fig. 1E, F). Accuracy of the SHIP-START model was 89.2% and of the SHIP-Trend model 86.8%.

Fig. 1: Effects of risk factors on TE events.
figure 1

Age- and sex-adjusted odds ratios (A, B), final model odds ratios (C, D) and receiver operating characteristic (ROC) curve (E, F) for SHIP-START-0 data (E) and SHIP-TREND-0 data (F). BMI body mass index, HCL hypercholesterolemia, RDW red cell distribution width, PLT platelet count, LYP lymphocyte ratio, AUC area under curve, CI confidence interval.

Red cell distribution width is a marker for the variation of erythrocyte size (anisocytosis) and used in combination with other laboratory markers for differential diagnosis of hematological diseases such as anemia and bone marrow dysfunction. Changes in RDW have been reported for a variety of chronic inflammatory conditions such as diabetes, cardiovascular disease, infections and cancer and its predictive and prognostic value has been reported for cardiovascular disease as well as for overall mortality of the general population [10]. Likewise, differential blood counts have been described as biomarkers of inflammatory processes and cancers. Identification of RDW, platelet counts and lymphocyte ratio as biomarkers for thromboembolic events in PV patients is therefore not surprising, as JAK2-mutated cancers are associated with broad activation of cell signaling [11] and increase of pro-inflammatory cytokines [3, 12]. Recently, exome-analysis studies have shown age-related clonal hematopoiesis (CH) in healthy individuals, driven by mutations of genes recurrently mutated in myeloid neoplasms and associated with an increased risk of hematologic cancer and cardiovascular disease. Critically, both SHIP-cohorts reported in this analysis have not been investigated for the presence of clonal hematopoiesis. Therefore, we cannot exclude the influence of CH on the predictive value of RDW and occurrence of TE events. Moreover, cutoffs for RDW may vary and have not been generally defined in previous analyses. Critical limit values of these potential biomarkers may depend on the underlying condition, comorbidities (e.g. previous TE complications) or concomitant medication. Finally, in SHIP-TREND, we used a broad definition of TE events (including peripheral thrombosis and thrombophlebitis) and predictive biomarker values may vary with a definition restricted to deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke. Of note, the allocation of individuals into the “TE-event” cohort based on the use of anticoagulants may result in inclusion of individual participants using ASA and P2Y-antagonists as primary rather than secondary prophylaxis.

Taken together, we could confirm RDW as an independent predictive parameter for thromboembolic events in the general population. Development and prospective validation of predictive scoring systems combining predictive laboratory parameters are clearly warranted but are beyond the scope of this report.

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Jaktinib shows promise in treatment of myelofibrosis

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June 23, 2023

David Statman

In this video, Idoroenyi Amanam, MD, discussed a study presented at ASCO Annual Meeting, examining the treatment of anemia in myelofibrosis patients.

Amanam, an assistant professor in the Division of Leukemia at City of Hope Cancer Center, highlighted a study that examined the effects of jaktinib (Suzhou Zelgen Biopharmaceuticals Co, Ltd) versus hydroxyurea in patients with intermediate to high-risk myelofibrosis, with a primary endpoint of spleen volume reduction.

“From a response and efficacy perspective, jaktinib appears to be promising,” Amanam said. “What they have right now is exciting, and it’s another option in a space where we don’t have too many options.”

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New and Anticipated Advances Across Hematologic Malignancies Necessitate Improved Navigation of Current Options

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June 23, 2023

Courtney Flaherty

Recent approvals of BTK inhibitors, antibody-drug conjugates, and other targeted therapies for B-cell malignancies have rapidly expanded the treatment armamentarium and improved the standard of care. With several more potentially paradigm-shifting approvals on the horizon, a nuanced understanding of current decision-making in the absence of optimal sequencing, as well as a renewed focus on incorporating these agents into clinical practice, is still required to improve patient outcomes in this space, according to John M. Burke, MD.

“A lot of promising drugs are in development or have been approved in B-cell malignancies, myelofibrosis, and polycythemia vera,” Burke said following an OncLive® State of the Science Summit™ on leukemia and lymphoma, which he chaired. “Treating physicians, oncologists, and hematologists should be aware of these new developments and [use this knowledge to] help their patients make informed decisions about what’s best for them in a particular situation.”

Burke expanded on key topics discussed by himself and his colleagues at the meeting in an interview with OncLive, including the use of novel BTK inhibitor regimens in mantle cell lymphoma (MCL), treatment sequencing challenges and other unmet needs indiffuse-large B-cell lymphoma (DLBCL), the evolution of management strategies for myeloproliferative neoplasms, and the potential influence of new and emerging therapeutics in chronic lymphocytic leukemia (CLL).

Burke is the associate chair of the Hematology Research Program for US Oncology, and a medical oncologist and hematologist at Rocky Mountain Cancer Centers in Aurora, Colorado.

OncLive: What BTK inhibitor studies have had the most influence on the treatment landscape in treatment-naïve and relapsed/refractory MCL?

Burke: In the treatment-naive space, the two recent trials that made a splash were [the phase 3] SHINE [NCT01776840] and TRIANGLE [NCT02858258] studies. Both [SHINE and TRIANGLE] showed that adding the BTK inhibitor ibrutinib [Imbruvica] to conventional therapy for transplant-eligible and -ineligible patients improved progression-free survival [PFS] and failure-free survival [in each respective trial]. Adding the BTK inhibitor to initial therapy [kept] patients in remission for a longer period. Those are important findings, and experts [in the] community are debating exactly how to incorporate them into practice. [This is] made more complex by the recent withdrawal of ibrutinib from the market for MCL. That’s added a little bit of complexity to decision-making when we treat these patients.

As for combination studies [in the] relapsed/refractory [setting], there’s studies of BTK inhibitors with venetoclax [Venclexta], [as well as] some with CD20[-directed] antibodies. There’s a lot of novel combinations being looked at in the relapsed space. None of them have recently led to new approvals, but we’re seeing exciting, chemotherapy-free regimens being used. There’s quite a lot of exciting [things] going on in MCL.

Could you highlight some of the factors that influence the selection of current BTK inhibitor regimens in MCL?

It depends on where the patient is in their disease course. For those who are treatment-naive, [you’d ask]: Is this someone where the potential benefits of adding a drug into the treatment program may outweigh any added risks? [Are they] transplant-eligible? What chemotherapy and immunotherapy partner [would] you administer along with the BTK inhibitor? In the patients [who are] relapsed/refractory, you’re thinking about what treatment they received before, and weighing the pros and cons. What are the benefits? What are the risks? Is this the best treatment for the patient at that time? What are their comorbidities? Those are all factors that [contribute to] the decision when you’re picking a regimen for a patient with relapsed MCL.

What ongoing or upcoming trials in MCL are you interested to see conducted?

One of the trials I’m excited about looks at the recently approved pirtobrutinib [Jayprica] and compares that with conventional BTK inhibitors in MCL. That’s the ongoing [phase 3 BRUIN-MCL-321] trial [(NCT04662255) assessing] how the new non-covalent BTK inhibitor pirtobrutinib compares [with] covalent BTK inhibitors.

At the 2022 ASH Annual Meeting, we saw a presentation [of findings from a single-arm, phase 2 study (NCT03863184)] on acalabrutinib [Calquence] in combination with lenalidomide [Revlimid] and rituximab [Rituxan] as an exciting, novel chemotherapy-free regimen. We’re [also] seeing trials of venetoclax in combination with BTK inhibitors with or without CD20 antibodies that look promising.

One wonders whether, and how much, chemotherapy is going to be used in the future with these promising novel agents emerging. Right now, chemotherapy is part of standard practice, but we’ll see how the field moves. It is moving towards an increasing use of novel targeted therapies.

Regarding your second presentation, what major changes have occurred for the management of relapsed/refractory DLBCL?

One huge paradigm shift that occurred about a year ago was the demonstration that [some] CAR T-cell products are superior to conventional salvage chemotherapy and stem-cell transplant in patients whose DLBCL relapsed within a year of initial therapy. The other thing we’re seeing is an increasing utilization of novel targeted agents in the relapsed setting. Examples of that are polatuzumab vedotin-piiq [Polivy] along with chemotherapy, tafasitamab-cxix [Monjuvi] along with lenalidomide, and loncastuximab tesirine-lpyl [Zylonta].

[Overall], a number of novel therapies have demonstrated benefit [in this space]. Recently [we had] the approval of the bispecific antibody epcoritamab-bysp (Epkinly) for patients with relapsed DLBCL. [This approval signals the start of] a new era where we’re hopefully going to see a few [more] bispecific antibodies being approved for relapsed DLBCL. Moving forward [we’ll also see attempts to] incorporate those effective agents into earlier lines of therapy to hopefully cure more people with DLBCL.

The other huge paradigm shift in DLBCL in the frontline [setting] is a demonstration of benefit [with] polatuzumab vedotin in combination with [rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP)]. [This was] compared with [cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine (R-CHOP), which] has been the standard therapy for several decades. The paradigm shifts in DLBCL [occurred in the] frontline, early relapse, and salvage [settings], with novel agents becoming available and taking the place of chemoimmunotherapy in relatively heavily pretreated patients.

Despite these advances, what unanswered questions remain in DLBCL?

[One] unanswered question will be: how do we sequence all these novel agents? That’s what everyone has been asking recently. In the past couple of years since we’ve seen approvals of [tafasitamab plus lenalidomide], [polatuzumab vedotin, bendamustine and rituximab (Pola-BR)], loncastuximab, selinexor [Xpovio], and now bispecific antibodies, [but we still don’t know if] there is a best sequence [of treatment options].

Another [unanswered question] is how can we utilize these [approved agents] more effectively? There are very few patients with relapsed DLBCL who benefit from all these drugs, because they don’t live long enough to receive all of them if they relapse. We need to do a better job of getting patients [earlier] exposure to these drugs to cure more people earlier.

How can these agents be incorporated [into clinical practice]? Ongoing studies have been [attempting to answer] that question for a couple of years and will continue to do so. For example, there’s been [the phase 3 frontMIND] trial [NCT04824092] of R-CHOP with or without tafasitamab and lenalidomide as a frontline therapy for DLBCL. [This study asks whether] we can and should incorporate that novel combination into the frontline setting to try to cure more people. [There is also] the use of pola-R-CHP in the frontline [setting], [which] bested R-CHOP in terms of PFS and changed the paradigm for frontline therapy in DLBCL. [Other unanswered] questions [include whether] we can incorporate bispecific [antibodies] into earlier lines, [whether] CAR T-cell therapy should be utilized earlier for patients with high-risk DLBCL or those who [don’t respond] well to initial R-CHOP, and [if] we can use novel therapies for elderly patients who can’t tolerate conventional R-CHOP chemotherapy. [There are] ongoing studies of loncastuximab and other [agents] in that space [to address this question.]

The key question here is: can we use some of these agents earlier in the treatment algorithm? Can we move these [approved agents] earlier [in the treatment course] and expose more patients to them to [help them] derive [more] benefit and hopefully [lead to more] cures.

Shifting to the presentation given by Christopher Benton, of Rocky Mountain Cancer Centers, how has the management of myelofibrosis changed in recent years?

Myelofibrosis is an interesting and changing disease. The JAK-2 inhibitor ruxolitinib [Jakafi] is the key drug approved for that disease, but there are a lot of promising new agents emerging. Examples include pacritinib (Vonjo) for those with low platelet counts, and we hope to see an approval soon for momelotinib, which might help patients with anemia. We saw a number of agents demonstrating benefit for patients with myelofibrosis in clinical trials, including improvement in anemia. One was called pelabresib [CPI-0610], and selinexor [also] looks promising.

[Overall, there are] a lot of promising agents that could help practitioners and patients overcome some of the problems that we [have in myelofibrosis]. Right now, we don’t have a great drug to treat anemia in patients with myelofibrosis and it’s a common [toxicity]. In fact, ruxolitinib can make anemia worse in patients with myelofibrosis. It would be great to have options [that] add to the benefit of ruxolitinib [but also] help people with anemia. Dr Benton reviewed several [agents] on the horizon [that] may be able to help folks with myelofibrosis.

How does the approval of zanubrutinib in CLL illustrate the importance of next-generation BTK inhibitors in that setting per the presentation given by Luke Mountjoy, of Colorado Blood Cancer Institute?

Zanubrutinib [Brukinsa] demonstrated benefit compared with chemoimmunotherapy, specifically BR, in treatment-naive CLL. [It also] led to improvements in PFS, [higher] response rates, and a more favorable toxicity profile compared with ibrutinib in the [phase 3] ALPINE study [NCT03734016] in patients with relapsed CLL. The next-generation BTK inhibitors including acalabrutinib [Calquence] and zanubrutinib have demonstrated enough favorable comparative results compared with ibrutinib, and most of us have transitioned from recommending ibrutinib to new patients to using one of the newer second-generation BTK inhibitors in that space.

As to whether patients who are on ibrutinib and doing fine should switch, [that] is a tougher question. My practice is not to do that, and most doctors I know are doing the same. But clearly the new, second-generation BTKs are here to stay and have some real advantages over ibrutinib for patients. They are probably the preferred BTK inhibitors for most people with CLL.

Dr Mountjoy also briefly touched on the phase 3 TRANSFORM study (NCT0357535) of lisocabtagene maraleucel (liso-cel; Breyanzi) in B-cell lymphoma. What data have been seen with the use of liso-cel so far, and what unmet needs could be addressed by the continued investigation of liso-cel in this space?

It’s an interesting backstory. Some of the first patients treated with CAR T-cell therapy had CLL and case reports [from a pilot, phase 1 study (NCT01029366) that] were published in the New England Journal of Medicine more than a decade ago. Ten-year follow up [data for] those patients were published about a year ago and showed that 2 individuals have no evidence of CLL in their bodies 10 years later, with evidence of CAR T cells still circulating. The presumption is that those patients are cured. With these initial extremely promising results, there was a hope and expectation that [CAR T-cell therapy was] going to be a homerun, and [that we’d] get the trials done and get it approved [quickly]. More than a decade later, the trials are still rolling along and nothing’s approved. [CAR T-cell therapy] is not available commercially for use for CLL.

In the session Q&A, we talked informally about why that is and [discussed] some of the challenges faced when treating [patients with] CLL and delivering these therapies in CAR T-cell trials. Liso-cel is demonstrating great promise and good results in CLL. [There are] still relatively small numbers of patients [being] reported in the trials, but [it is] showing good enough results where there’s still optimism and hope that CAR T-cell therapy will become available and utilized in CLL.* Perhaps [it will not be used] for most patients but certainly [could be an option] for those whose disease is very aggressive, continues to relapse, and is threatening their lives. CAR T-cell therapies, like liso-cel, offer promise for these patients.

Would you like to highlight any trials in the field of hematologic malignancies that are being conducted at your institution?

It’s a complex field, and it’s tough to stay up on everything, but [these advances are] exciting.

One trial I would choose to highlight would be the pirtobrutinib vs other BTK inhibitor trial in MCL that I mentioned earlier. It’s not the most common disease or situation, but if I had relapsed MCL [that study] is one that I would choose to go on.

I also [want to] highlight some ongoing trials in other lymphomas. We have [the phase 2 LOTIS-9 trial (NCT05144009)] in DLBCL with loncastuximab plus rituximab [in] elderly [patients]. I find that one to be particularly exciting because elderly patients with DLBCL are not well served by current standards of care, if there is such a thing. We need better treatments for [this population].

Everyone is excited about bispecific antibodies, and we have some very exciting bispecific antibody trials of both mosunetuzumab [Lunsumio] and epcoritamab in various lymphomas in various stages. Some [involve] treatment-naive patients, and some [are enrolling those with] relapsed/refractory disease. [Ultimately, there are] a lot of fun [trials] going on.

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