• Center on Health Equity and Access
  • Clinical
  • Health Care Cost
  • Health Care Delivery
  • Insurance
  • Policy
  • Technology
  • Value-Based Care

Conference Coverage: European Hematology Association 2023 Hybrid Congress

Evidence-Based OncologyAugust 2023
Volume 29
Issue 7
Pages: SP599-SP610

Full team coverage from the European Hematology Association 2023 Hybrid Congress, which took place June 8-11 in Frankfurt, Germany.

Phase 3 CARTITUDE-4 Results Show Superiority of Cilta-Cel in MM

The first phase 3 results from the CARTITUDE-4 trial of ciltacabtagene autoleucel (cilta-cel; Carvykti) vs standard of care (SOC) in lenalidomide-refractory multiple myeloma (MM) demonstrated the former’s convincing superiority in several key outcomes.1

EHA logo

Presented during the June 10 plenary session at the European Hematology Association 2023 Hybrid Congress by Hermann Einsele, MD, of University of Würzburg in Germany, the data could position the chimeric antigen receptor (CAR) T-cell therapy as the new SOC. They extend the findings of the phase 1b/2 CARTITUDE-1 trial (NCT03548207), which showed cilta-cel’s efficacy in extending progression-free survival (PFS) for patients with MM who had received at least 3 prior lines of therapy.4

Results for CARTITUDE-4 were also presented in a late-breaking abstract at the American Society of Clinical Oncology Annual Meeting in Chicago, Illinois, on June 5, 2023.2 Cilta-cel was approved for treatment of relapsed or refractory MM in March 2022 based on the results of CARTITUDE-1, including an objective response rate of 98%.3

CARTITUDE-4 (NCT04181827) compared cilta-cel’s efficacy and safety vs that of SOC (pomalidomide [Pomalyst], bortezomib [Velcade], and dexamethasone; or daratumumab [Darzalex], pomalidomide, and dexamethasone) in patients with lenalidomide-refractory MM who had 1 to 3 prior lines of therapy. The primary end point was PFS; secondary end points included safety, patient-reported outcomes, and efficacy as measured by complete response, overall response rate, overall survival, and minimal residual disease (MRD) negativity.

Investigators randomly assigned 208 patients to the cilta-cel arm and 211 to the SOC arm, representing the intent-to-treat population. Baseline demographics and disease characteristics were similar across arms, Einsele said.

The median PFS was 11.8 months in the SOC arm and not reached in the cilta-cel arm, thus meeting the study’s primary end point; 49% and 76% of patients in each arm, respectively, achieved PFS at 12 months. Cilta-cel had the edge on PFS regardless of whether patients had 1 or 2 to 3 prior lines of therapy, and even those who received cilta-cel after 2 or 3 other therapies had better PFS than those who received SOC after just 1 prior line. The CAR T-cell therapy also had a significantly higher overall response rate (OR, 3.0) and MRD negativity rate (OR, 8.7) vs the SOC.

Moving into the safety data, Einsele showed that most treatment-emergent adverse events in the cilta-cel arm were hematological, often neutropenia. Of note, there were 7 deaths due to COVID-19 in the cilta-cel arm and 1 in the SOC arm.

“The issue of COVID-19 really indicates the need for strict prevention measures and aggressive treatment for COVID-19 in patients who are receiving CAR T-cell therapy,” Einsele said. “When safety measures consistent with the international guidelines were introduced, there were no further COVID-19–related deaths in the cilta-cel arm.”

Drawing comparisons between CARTITUDE-14 and CARTITUDE-4, he noted a lower incidence and severity of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, movement and neurocognitive treatment-emergent adverse events, and some cytopenias in the newer trial, suggesting improved tolerability of cilta-cel when used in earlier lines of therapy.

“In conclusion, cilta-cel has the potential to be a new [SOC] for patients with lenalidomide-refractory [MM] after first relapse,” Einsele said.

Plenary moderator Brian Huntly, MB ChB, PhD, of the University of Cambridge in England, posed a question to Einsele: With results this impressive, why qualify that prediction with “potential” or “probably”?

Einsele said that he would like to see longer follow-ups, but so far, “this extremely high overall response rate in the patients who were treated with cilta-cel speaks for using CAR T cells in early lines of therapy.” 

1. Einsele H, Yong K, Harrison S, et al. First phase 3 results from CARTITUDE-4: cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. Presented at: European Hematology Association 2023 Congress; June 8-11, 2023; Frankfurt, Germany.
2. Dhakal B, Yong K, Harrison SJ, et al. First phase 3 results from CARTITUDE-4: cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 17):LBA106. doi:10.1200/JCO.2023.41.17_suppl.LBA106
3. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. News release. FDA. Updated March 7, 2022. Accessed July 3, 2023. https://bit.ly/3PD4JZ1
4. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8

Burgeoning Immunotherapy Options in Oncology Move Beyond CAR T and Usual Disease States

The use of immune therapies for hematological malignancies is expanding beyond chimeric antigen receptor (CAR) T-cell therapies in the traditional lymphoid disease states, but the impact on patient quality of life must remain top of mind, according to experts during a session at the European Hematology Association (EHA) 2023 Congress in Frankfurt, Germany.



Hermann Einsele, MD, FRCP, session chair and professor of internal medicine at Universität Würzburg in Germany, kicked off the session by noting that despite the intense attention on CAR T-cell therapies in recent years, they are not the only immunological therapy available, and that there have been many developments in other areas.

One such development is the use of T-cell receptor (TCR)–engineered T cells, in which the cells are manipulated ex vivo to express certain TCRs, explained the first presenter, Emma Morris, PhD, professor of clinical cell and gene therapy at University College London in England. T-cell signaling is complex, she said, and the arrangement of receptors is important in the downstream signaling pathway.

TCRs are human leukocyte antigen (HLA) restricted, which “makes the translation of these therapies difficult, because the recipient has to express the same HLA molecules,” Morris said. However, the advantages of TCRs include their ability to recognize neoantigens in the cancer mutagenome, making them better at discriminating these tumor cells.

Alongside the refinement of CAR T-cell therapies into the next generation that can recognize abundant cell surface antigens, the same approaches are being used to improve next-generation TCR T cells by optimizing TCR pairing and preventing mispairing, which can be achieved through the use of CRISPR or other gene editing approaches.

Morris highlighted several examples of ongoing research in the TCR space, such as the investigation of whether adding more CD3 to the TCR complex could enhance the therapeutic effect without increasing mispairing. Investigators are also looking into whether TCR-based therapy could target solid tumors more effectively than CAR T.

For instance, in a 2022 study, Ruggieri et al demonstrated the promise of a genome editing approach that could avoid mispairing and maximize TCR expression and function, which showed efficacy in killing acute myeloid leukemia (AML) blasts, acute lymphoblastic leukemia blasts, and glioblastoma cells in vitro and in vivo.1 Also published last year was a study by Omer et al that used a costimulatory CAR to boost the activity of T cells expressing TCRs, which enhanced antitumor response.2

Although Morris said TCRs are not yet ready to challenge CAR T for dominance in the immunotherapy space, investigators are “trying to target difficult solid tumors in a hostile microenvironment where we have to use all these novel engineering techniques, because, remember, the [TCR] is fantastic; it’s why our T cells work…. They are exquisitely sensitive, exquisitely discriminating, and [they are] able to recognize very low levels of target antigen.”

The next speaker, Stephan Mielke, MD, professor of hematology and cell therapy at the Karolinska Institutet in Stockholm, Sweden, began his presentation by recalling that at an EHA Congress 6 years ago, he delivered a talk on how to build a CAR T-cell therapy center. Today, such a talk would draw no audience, as the number of centers has already exploded.

Mielke explains CAR T-cell engineering to patients as giving their cells glasses to make them see something they otherwise wouldn’t, as they usually look intracellularly. This approach has demonstrated incredible results, largely in lymphoid malignancies and with mechanisms that target CD19 or B-cell maturation antigen, but there are still unmet needs.

“When we get a new tool, like CAR T cells, targeted therapy, or checkpoint inhibitors, we always have the mindset [of] ‘Now we’re going to cure cancer; we’re going to use it for all the diseases.’ But then we are learning that it will not work for all diseases,” Mielke said. For instance, AML is difficult to treat because the tumor lacks perfect antigens, but IL1RAP could be an ideal target for CAR T cells in this disease state because its expression is restricted to malignant cells and monocytes.

Solid tumors are even more difficult to treat with CAR T cells, he continued, due to several factors including T-cell dysfunction within the tumor microenvironment, and that one side of a tumor might have completely different antigen expression than the other side of the tumor.

Some ongoing subjects of investigation that Mielke highlighted included BNT211-01 (NCT04503278) which showed an ongoing effect of CAR T cells in testicular cancer; NY-ESO-1 as a target in patients with sarcoma; and CD70, which he called “a promising pan-cancer antigen” that can be found in the vast majority of tumors. Future directions for research on CAR Ts could include CRISPR engineering and use in combination with checkpoint inhibitors or radiotherapy.

He concluded by thanking the patients who put their trust in the clinicians and investigators working on CAR T therapies, which obligates them to share these findings at conferences for the benefit of their patients.

The session ended with the perspective of a patient advocate, Hans Scheurer, who has had myeloma since 2005 and is currently chair of the Workgroup of European Cancer Patient Advocacy Networks. He emphasized that quality of life is the key end point for patients with cancer. Measuring value by patient experience can be difficult and is often labeled as subjective, he said, but that’s not an excuse for regulators to refuse to collect and use these data. “Avoiding it is not helping you get a better insight on its value of making real differences,” Scheurer said. For instance, clinicians may assume that patients will universally want a therapy that can extend their life, but in actuality, some patients will not want to undergo severe adverse effects for just a few more months of survival.

Myeloma Patients Europe, which Scheurer served as president of from 2016 to 2022, interviewed 11 patients receiving CAR T-cell therapies who praised the good quality of life yielded by the treatment. One patient was quoted as saying, “For the first time, I felt as good as before my diagnosis.”

Some drawbacks reported by the patients included travel time to the CAR T center, fear of disease progression while the cells are being modified in the laboratory, and the immune vulnerability that comes with the treatment approach, which is of particular concern as society is largely moving past the COVID-19 pandemic precautions.

The takeaways from patients are that although they’re excited by the impressive results of immunological approaches to cancer, they want more research on the variation in adverse effects during treatment and beyond, as many are concerned about long-term brain effects and immune effector cell-associated neurotoxicity syndrome.

From the clinician’s perspective, Morris asked Scheurer what types of factors go into patients’ decisions to take part in a phase 1 trial. Most commonly, patients joining these early-stage trials have run out of other treatment options, he said, but transparency is key to making an informed decision.

"Have that conversation and be honest about what you offer, not only [about the] data on a few extra months [of survival] but [also about] what the impact [of having these adverse effects has] on your life,” he said. 

1. Ruggiero E, Carnevale E, Prodeus A, et al. CRISPR-based gene disruption and integration of high-avidity, WT1-specific T cell receptors improve antitumor T cell function. Sci Transl Med. 2022;14(631):eabg8027. doi:10.1126/scitranslmed.abg8027
2. Omer B, Cardenas MG, Pfeiffer T, et al. A costimulatory CAR improves TCR-based cancer immunotherapy. Cancer Immunol Res. 2022;10(4):512-524. doi:10.1158/2326-6066.CIR-21-0307

Late-Breaking Abstracts Offer Sneak Peek at Future of Hematology

The June 11 late-breaking oral session at the European Hematology Association (EHA) 2023 Hybrid Congress featured new data from 5 abstracts submitted after the meeting’s deadline, including outcomes from trials in polycythemia vera, acute myeloid leukemia (AML), and more.

Session cochair Konstanze Döhner, MD, of the University Hospital Ulm in Germany, introduced the abstracts and noted that they were selected by the scientific committee and advisory board for their high relevance to the hematological community and their diversity of countries, disease states, and type of research.

Rusfertide in polycythemia vera. Marina Kremyanskaya, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, presented findings from a withdrawal analysis of the phase 2 REVIVE study (NCT04057040) of rusfertide (PTG-300),1 a hepcidin memetic used to control hematocrit levels in patients with polycythemia vera who had a high phlebotomy burden. Patients received a subcutaneous injection once weekly then were randomly assigned at week 29 to either receive placebo or maintain the rusfertide dose.

Rusfertide met its primary efficacy end point of response, which was defined as patients not needing phlebotomy within 12 weeks (69.2% vs 18.5% in the placebo arm; P = .0003). The investigational drug was generally well tolerated, with 83% of the treatment-emergent adverse events (TEAEs) being grade 1 or 2; there were no grade 4 or 5 TEAEs.1

“Rusfertide demonstrated favorable effects on several patient-reported outcomes, such as fatigue, problems with concentration, pruritus, and inactivity, and that was particularly seen in patients who had more severe symptoms at baseline,” Kremyanskaya said. She noted that the phase 3 VERIFY trial (NCT05210790) is investigating rusfertide vs placebo, and there is a follow-on 2-year extension study opening this year for the patients who completed the REVIVE study.

Gilteritinib in FLT3-ITD AML. Mark J. Levis, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, presented findings from the phase 3 BMT CTN 1506/MORPHO trial (NCT02997202). This was a randomized trial of the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib as posttransplant maintenance therapy for FLT3-internal tandem duplication (ITD) AML, a particularly aggressive disease.2 These patients have a high rate of relapse, Levis noted, especially if they have minimal residual disease (MRD) before transplant.

In the worldwide randomized controlled trial, gilteritinib narrowly missed the primary end point of relapse-free survival, with an HR of 0.679 but a P value of .0518. However, the benefit of gilteritinib varied by region and MRD status. Patients with MRD tend to benefit from the drug, whereas the benefit is unclear for those without MRD. There was also greater separation of the survival curves between the arms in North American patients vs those in Europe and especially in Asia.2

“Yes, the study did not meet its primary end point, but I think this was a successful study,” Levis said. “We learned how to use the drug and in whom.… [Gilteritinib] should be standard of care for those who are MRD positive.”

Gilteritinib was previously approved as Xospata (Astellas) for patients with relapsed or refractory (R/R) FLT3-mutated AML.3

Ziftomenib in MPN1-mutated AML. Also presenting findings relating to AML was Amir Fathi, MD, of Massachusetts General Hospital in Boston. He presented data on the menin inhibitor ziftomenib in adults with R/R NPM1-mutated AML, noting that there is no currently approved treatment targeting this mutation. Focusing on the phase 1b expansion of the KOMET phase 1/2 study of ziftomenib (NCT04067336) in a heavily pretreated and heavily comutated patient population, Fathi discussed the activity and tolerability of the agent.4

No new safety signals were observed, with the most common adverse events being nausea and differentiation syndrome, and there was encouraging clinical activity, with approximately one-third of participants achieving complete remission and a 45% overall response rate, he said.
Not for the first time in data readouts at EHA 2023, the findings included a patient who was showing a promising response to treatment but then died of COVID-19 infection, offering a somber reminder of the pandemic’s lasting impact on scientific research.

“Resistance mutations have developed infrequently, and ziftomenib retains activity against common menin gatekeeper mutations,” Fathi said. He mentioned that the phase 1 KOMET-007 study (NCT05735184) is open for enrollment and will study ziftomenib in combination with chemotherapy in patients with newly diagnosed or relapsed AML who have certain mutations.

Cevidoplenib in chronic ITP. Jun Ho Jang, MD, PhD, of Samsung Medical Center in Seoul, South Korea, delivered data on cevidoplenib, a novel selective inhibitor of spleen tyrosine kinase, in persistent and chronic immune thrombocytopenia (ITP). Chronic ITP is an orphan disease with an unmet need for emerging therapies, so investigators in this phase 2 trial aimed to evaluate its performance on an end point of increasing platelet count past 30,000 per μL and doubling platelet count from baseline.5

Cevidoplenib was associated with a numerically greater rate of platelet response vs placebo (400 mg: 63.6%; 200 mg: 46.2%; placebo: 33.3%), but the difference was not statistically significant for either dose. Patients who sustained their platelet count, defined as having counts above 50,000 per μL at 4 or more of their previous 6 visits, made up 27.3% of the 400-mg arm and 19.2% of the 200-mg arm; no patients in the placebo arm achieved this outcome.5

“The results of the study warrant further clinical studies in a larger number of participants for an extended period to confirm durability of the clinical benefits,” Jang said.

Proof of concept in PNH. Jens Panse, MD, of the University of Aachen in Germany, presented interim findings from a proof-of-concept trial of OMS906, a MASP-3 inhibitor, which was used to normalize hemoglobin levels in patients with paroxysmal nocturnal hemoglobinuria (PNH).6 PNH is a rare and life-threatening disease that can lead to fatigue, anemia, and thrombosis, and there is an unmet need for novel complement inhibitors. After another investigation found OMS906 to be well tolerated in healthy patients, this study looked at 10 treatment-naïve patients with PNH.

In terms of safety, it appeared to be well tolerated, with 2 patients reporting headache and 3 reporting itching, but there were no major TEAEs. Its efficacy also appeared promising, as all patients without myelodysplastic syndrome reached hemoglobin levels considered normal.6

“OMS906 dose escalation guided by the [pharmacokinetics and pharmacodynamics] of patients experiencing subclinical hemolysis is underway to inform achievement of quarterly dosing,” Panse said. He closed his presentation by giving special thanks to the patients and health care professionals in Ukraine who participated in this study, notably lead investigator Oksana Karnabeda, MD, of Bogomolets National Medical University in Kyiv.

In response to a question from session cochair Brian Huntly, MBChB, PhD, of the University of Cambridge in England, Panse speculated that if these findings are confirmed in larger trials, “we might be able to achieve sustained complement inhibition by giving 4 subcutaneous doses per year, which might lead to very valuable options for patients if they have the choice of all. I’m always reminded that 80% of the world does not have access to any complement inhibitor.” 

1. Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rusfertide: blinded randomized withdrawal results of the REVIVE study. Presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2710. Accessed July 18, 2023. https://bit.ly/3DpJ3rL
2. Levis M, Hamadani M, Logan B, et al. BMT-CTN 1506 (MORPHO): a randomized trial of the FLT3 inhibitor gilteritinib as post-transplant maintenance for FLT3-ITD AML. Presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2711. Accessed July 18, 2023. https://bit.ly/3Ol0cJq
3. Pulte ED, Norsworthy KJ, Wang Y, et al. FDA approval summary: gilteritinib for relapsed or refractory acute myeloid leukemia with a FLT3 mutation. Clin Cancer Res. 2021;27(13):3515-3521. doi:10.1158/1078-0432.CCR-20-4271
4. Fathi A, Wang E, Issa G, et al. Activity, tolerability, and resistance profile of the menin inhibitor ziftomenib in adults with relapsed/refractory NPM1-mutated AML. Presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LB2713. Accessed July 18, 2023. https://bit.ly/3XV7w1C
5. Jang JH, Grosicki D, Cheong JW, et al. Cevidoplenib, a selective inhibitor of spleen tyrosine kinase (SYK), in persistent and chronic immune thrombocytopenia (ITP): efficacy and safety in a multicenter, placebo-controlled phase 2 study. Presented at: European Hematology Association 2023 Hybrid Congress; June 8-15, 2023; Frankfurt, Germany. Abstract LBA2712. Accessed July 18, 2023. https://bit.ly/3XYychX
6. Kamabeda O, Gavriilaki E, Nangia N, Whitaker S, Panse J. OMS906, a mannan-binding lectin-associated serine protease-3 (MASP-3) inhibitor, normalizes hemoglobin levels in treatment-naïve PNH patients: interim data from a proof-of-concept clinical trial. Presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2714. Accessed July 18, 2023. https://bit.ly/44sVDCx

Experts Spar Over Role of Real-World Data as Replacement for Clinical Trials in Hematology

Participants in a friendly debate at the European Hematology Association 2023 Congress in June focused on the potential for real-world data to improve the generalizability of clinical trial results but also acknowledged the current challenges in collecting and standardizing these data.



Moderator Philippe Rousselot, MD, PhD, of the Université de Versailles Saint-Quentin-en-Yvelines in Paris, France, set the stage by discussing the considerable attrition seen in clinical trials, where the rule is that 1 patient is analyzed for every 10 identified. Involving patients more and incorporating their input in a trial may help improve that rate, he said.

Further, the real world data carries much more variability because clinical trials have eligibility criteria that often exclude older patients or those with comorbidities, which affects the generalizability of clinical trial results, he said. In other words, Rousselot noted, there is a continuum with sensitivity at one end, where clinical trials aim to detect an intervention’s superiority, and applicability at the other, with pragmatic trials closer to approximating the real world.

With this tension in mind, he asked the audience, “Can we use real-world data instead of clinical trials?” Forty-five percent of respondents voted yes and 55% voted no.

There to argue the “no” position was Martin Dreyling, MD, a professor of medicine at Ludwig-Maximilians-Universität München in Munich, Germany.

“There is no alternative to clinical trials,” he said, presenting a slide of a pyramid ranking meta-analyses as the highest-quality evidence, with those meta-analyses composed of individual randomized controlled trials. To prove the point that high-quality evidence is of utmost importance, he asked the audience to raise their hands if they don’t believe in evidence-based medicine; no one did.

Case studies do have a place in formulating the hypotheses investigated in trials, he said, but only randomized prospective trials can balance for the known and unknown risk factors that determine outcomes. Cohort studies can account for known risk factors, but no one knows everything about medicine, he said.

His work with the European Consortium on Reducing Bureaucracy in Clinical Trials has informed his view that instead of doing away with clinical trials because they don’t translate to the real world, trial participant pools instead should represent the general population, he said.

On the contrary, argued Carsten Niemann, MD, PhD, a clinical associate professor at the University of Copenhagen in Denmark, investigators have to use real-world data to provide evidence of how something works for actual patients. He picked as an example the TRIANGLE trial (NCT02858258)—not coincidentally, led by Dreyling—of autologous stem cell transplantation vs ibrutinib in mantle cell lymphoma and asked the audience if these participants represent their patients with the disease. Those who don’t meet clinical trial inclusion criteria have much poorer survival outcomes, and half of Danish patients with multiple myeloma wouldn’t meet typical trial criteria, he noted. Clinical practice has historically been informed by “the medical art” of incorporating education, training, experience with patients, and discussion with colleagues, Niemann said, but now with the advent of time-series data and genomics, we are moving into the age of the data-driven medical art. Using technology to identify patterns within broad sources of data can overcome the criticisms of real-world data as low-quality, anecdotal evidence, he said.

He highlighted his work with the DALY-CARE cohort of Danish lymphoid cancer research, which links a biobank of tissue samples, national health registries, electronic health record data, and other data sources to determine which patients benefit from which intervention and informs clinicians how to treat them.

Niemann proposing inverting the evidence pyramid shown by Dreyling so that the top spot is held by the reality for real-world patients, followed by the truth for clinical trial patients, and finally at the bottom are the accepted beliefs in medical textbooks.

“We need to represent our patient population, and we need to do pattern recognition to adjust for all the problems with real-world data,” he concluded.

Moving into the debate portion, Rousselot asked participants about their predictions for the next 10 years as targeted therapies increase the number of available treatment options and decrease the number of patients eligible for each trial.

Dreyling said that it may have been easier to perform trials back when there was 1 drug for treating myeloma and 1 for treating lymphoma, but now that we have the ability to segment patients into subsets such as p53 alterations within rare diseases, it makes clinical trial design more complicated but still feasible if the framework is improved to reduce bureaucracy.

In response, Niemann argued that we also need evidence for approaches that haven’t been tested in clinical trials, such as medical devices and decision support tools. New technologies, often supported by artificial intelligence, can connect the patterns leading to outcomes that can be extrapolated to the real-world population outside of clinical trials, he said.

Regulatory bodies have an important role in this aim as well, he added, because data-driven pattern recognition will be more feasible if the FDA and European Medicines Agency make it mandatory to collect and standardize these data.

In response to an audience question, both speakers expressed skepticism of real-world evidence coming from social media, in part because of the potential bias: Patients who are able to log in and report their experiences are more likely to be having a better outcome.

There are also legal considerations around both types of data, the panelists agreed, which can make pharmaceutical companies hesitant to release their clinical trial data for real-world research. But these data are necessary,

Niemann said, “to make sure that we can actually improve treatment for our patients, that we can identify the subgroups that we need to model and identify and treat differently.”

Another audience member raised concerns about reliability in real-world data collection, but Niemann noted that adverse events reported in clinical trials can vary in classification, whereas medical histories can show, for instance, the timing of infection based on blood cultures being drawn and antibiotics being prescribed.

Polled again on whether they thought real-world data can replace clinical trials, the audience shifted toward Dreyling’s perspective, with 25% saying yes and 75% no. Satisfied that the attendees at least saw the advantages of both, the 2 experts shook hands, concluding the debate. 

Long-Term Data Show QOL Advantage of Zanubrutinib in 3 Cancers

Results from a long-term follow-up of the ASPEN trial of zanubrutinib (Brukinsa) in Waldenström macroglobulinemia (WM) showed greater improvements in quality of life (QOL) vs ibrutinib (Imbruvica). In addition, data from the ALPINE trial showed zanubrutinib’s QOL advantage in relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The posters were presented at the European Hematology Association 2023 Congress, held in Frankfurt, Germany, in June. The meeting’s agenda focused on incorporating patient-reported outcomes and real-world data in hematology and oncology.

The first abstract contained findings from the long-term follow-up of the phase 3 ASPEN trial (NCT03053440), which compared zanubrutinib and ibrutinib in patients with WM, looking specifically at a cohort of 201 patients with activating mutations in MYD88.1 Patients in the zanubrutinib (n = 102) and ibrutinib (n = 99) arms were asked to complete 2 health-related QOL (HRQOL) questionnaires at baseline, at every 3 cycles up to cycle 13, and every 6 cycles subsequently.

Baseline characteristics were largely similar between the arms, although the zanubrutinib arm had more patients older than 75 years (33.3% vs 22.2%) and more patients with anemia (65.7% vs 53.5%). Adherence rates were high in both arms, but the ibrutinib arm had more adverse events (AEs) leading to dose holds or reductions, drug discontinuation, or deaths.1

By cycle 4, patients taking ibrutinib were significantly more likely to experience diarrhea and nausea/vomiting than those taking zanubrutinib.

The gap between the arms closed as the cycles went on, with those symptoms staying stable in the zanubrutinib arm and ameliorating in the ibrutinib arm. Other symptoms improved from baseline in both groups but did not differ significantly between the arms.1

The zanubrutinib arm had a shorter median time to very good partial response (VGPR), at 8 months vs 17 months, and the combined complete response and VGPR rate was higher (38.2% vs 25.3%; P = .0374). The 31 patients taking zanubrutinib who achieved VGPR by cycle 25 generally had better patient-reported outcomes.1

Among just those who achieved VGPR, the zanubrutinib arm had higher physical functioning scores than the ibrutinib arm and lower fatigue scores, both at cycle 7 (difference in physical functioning, 10.42; 95% CI, 0.57-20.28; P = .0387; difference in fatigue, –11.76; 95% CI, –22.24 to –1.28; P = .0288) and at cycle 25 (physical functioning, 10.45; 95% CI, 0.12-20.79; P = .0476; fatigue, –13.53; 95% CI, –25.00 to –2.06; P = .0220). The zanubrutinib arm also compared favorably in terms of diarrhea and nausea/vomiting symptoms at cycle 4.1

“The improved HRQOL seen with zanubrutinib among patients who achieved VGPR by cycle 25 is consistent with the shorter median time to VGPR in the zanubrutinib arm and suggests that when disease is controlled to a similar extent, patients fare better in overall HRQOL when treated with zanubrutinib vs ibrutinib,” the poster concluded.1 The authors noted that these responses support the use of zanubrutinib as an effective Bruton tyrosine kinase inhibitor therapy option in WM.

The second abstract also assessed health-related QOL in zanubrutinib vs ibrutinib, this time using data from the phase 3 ALPINE study (NCT03734016) of patients with relapsed/refractory CLL or SLL.2 It contained data through the August 8, 2022, cutoff for a progression-free survival analysis of zanubrutinib, at which point the participants had a median of 29.6 months follow-up time.

The zanubrutinib (n = 327) and ibrutinib (n = 325) arms were largely similar in composition and had similar symptom scores at baseline. More patients in the ibrutinib arm discontinued therapy because of AEs than in the zanubrutinib arm (22.2% vs 15.4%).2

The main analysis focusing on efficacy found that zanubrutinib demonstrated superiority in terms of overall response rate (86.2% vs 75.7%; P = .007) and progression-free survival (HR, 0.65; 95% CI, 0.49-0.86; P = .0024), but the aim of this poster was to assess HRQOL. Like the ASPEN poster, it used validated scales, including the EuroQoL EQ-5D 5-L visual analogue scale, to have patients to rate their current general health, and the global health status, functioning, and symptom scores of the EORTC Quality of Life Questionnaire.2

By cycle 7 (6 months), global health status scores had significantly improved with zanubrutinib vs ibrutinib (difference, 3.00; 95% CI, 0.23-5.77; P = .0338); by cycle 13, 6 months later, the improvement in scores was still in favor of zanubrutinib but no longer significant (1.34; 95% CI, –1.37 to 4.06).2

At both cycles 7 and 13, the patients receiving zanubrutinib reported clinically meaningful improvements (≥ 5% mean change) from baseline in pain, fatigue, and physical and role functioning, but the between-arm differences were not significant. Mean visual analogue scale scores improved more in the zanubrutinib arm at both cycle 7 (7.92 vs 3.44) and cycle 13 (7.75 vs 3.92).2

The authors noted that both arms had generally good HRQOL at baseline, which could be why the differences between the arms were small and nonsignificant. However, they noted that patient-reported end points continued to improve in the zanubrutinib arm throughout the duration of treatment, suggesting that the Bruton tyrosine kinase inhibitor “positively affected HRQOL and that HRQOL improved over time.”2

The authors noted that they hope longer-term follow-ups and further analyses linking patient-reported outcomes to clinical end points will shed additional light on the extent to which zanubrutinib improves HRQOL.2

1. Tedeschi A, Tam CS, Owen RG, et al. Health-related quality of life in patients with Waldenström macroglobulinemia (WM) treated with zanubrutinib vs ibrutinib: results from the phase 3 ASPEN trial long-term follow-up. Poster presented at: European Hematology Association 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany.
2. Eichhorst B, Lamanna N, O’Brien SM, et al. Zanubrutinib vs ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): impact on health-related quality of life (HRQoL). European Hematology Association Congress 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany. Poster P640.

New Epcoritamab Data Show Strong Results in B-Cell Lymphomas

Newly released data from the ongoing phase 1/2 EPCORE NHL-2 (NCT04663347) trial show the T-cell–engaging bispecific antibody epcoritamab-bysp (Epkinly) led to a high overall response rate (ORR) and complete metabolic response (CMR) rate when used in combination with rituximab (Rituxan) and lenalidomide (Revlimid) in patients with relapsed or refractory follicular lymphoma (R/R FL).1

The new data were presented at the European Hematology Association (EHA) 2023 Congress, which was held on June 8 to 11, 2023, in Frankfurt, Germany. The FL news was presented alongside updated data from the EPCORE NHL-1 expansion cohort, which showed that the therapy led to deep and durable responses in patients with R/R large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma.2

The drug’s developers, Genmab A/S and AbbVie, also announced in a press release that they had dosed their first patients in the phase 3 EPCORE DLBCL-2 trial (NCT05578976) and the phase 2 EPCORE DLBCL-3 trial (NCT05660967), both of which will evaluate the safety and efficacy of the therapy as a first-line treatment in adults and older patients with DLBCL.3Discussing the FLresults, Anna Sureda, MD, PhD, of the University of Barcelona, and colleagues, explained that patients with FL are typically treated with chemoimmunotherapy, according to the release. However, approximately 1 in 5 patients experience progression within 24 months of their initial treatment, and early progression is a strong predictor of poor outcomes.

Epcoritamab, which is administered subcutaneously, demonstrated antitumor activity and a manageable safety profile as a single agent in patients with R/R FL, the authors said, but it has also shown promise in combination therapies.

The newly released data report on a pooled analysis of the 2a and 2b cohorts from the ongoing phase 1/2 EPCORE NHL-2 trial. In the study, patients with CD20-positive R/R FL received epcoritamab plus rituximab and lenalidomide (R2) for twelve 28-day cycles. The dosing schedule varied between the 2 cohorts.

Among 109 patients who received the therapy in the trial, the median age was 65 years. More than half (56%) of the patients had Follicular Lymphoma International Prognostic Index scores of 3 to 5, 61% had stage IV disease, and most (59%) had only 1 prior line of treatment. The vast majority (92%) had received alkylating agents, 62% had received anthracyclines, and 2 patients had previously received chimeric antigen receptor T cells.

The investigators reported an ORR of 98% and a CMR rate of 87% among the 104 patients whose responses were evaluable. Those findings held up across subgroups. Among patients who experienced progression within 24 months after their initial therapy, the investigators found a 98% ORR and a 75% CMR rate. In patients who were refractory to both an anti-CD20 and an alkylating agent (double refractory), the ORR was 95% and the CMR rate was 75.7%. In primary refractory patients—those with no response at 6 months or who relapsed within 6 months—the ORR was 100% and the CMR rate was 83.8%. In patients who were refractory to prior anti-CD20 therapy, the ORR was 96% and the CMR rate was 80.9%.

“The results being presented today are encouraging and warrant further evaluation of epcoritamab in combination with R2 in this patient population to determine [whether] this combination could potentially be offered as a treatment option for patients in need of alternative therapeutic options,” Sureda said in the company statement.3

In terms of safety, the most common treatment-emergent adverse events (AEs) were neutropenia (57%), cytokine release syndrome (CRS; 48%), injection-site reactions (41%), and fatigue (36%). Most of the cases of CRS were grade 1 or 2, and most occurred following the first dose. No patients discontinued treatment as a result of AEs. Two patients experienced immune effector cell-associated neurotoxicity syndrome, though both cases resolved.

In addition to the R/R FL data, investigators also presented updated data



from the EPCORE NHL-1 LBCL expansion cohort.2 Like results published earlier this year, the new data showed epcoritamab led to deep and durable responses.4 At a median follow-up of 20 months, the new data showed an ORR of 63.1% and a complete response (CR) rate of 39.5% in patients with R/R LBCL, and a 61.9% ORR and 39.6% CR rate in patients with R/R DLBCL. The median overall survival times were 18.5 months and 19.4 months, respectively.

Judith Klimovsky, MD, the executive vice president and chief development officer at Genmab, said Genmab and AbbVie remain committed to evaluating the therapy. “The data being presented at EHA demonstrate our shared commitment to development of epcoritamab as a potential core therapy for B-cell malignancies,” Klimovsky said. 

1. Sureda A, Falchi L, Leppä S, et al. Epcoritamab with rituximab + lenalidomide (R2) provides durable responses in patients with high-risk follicular lymphoma, regardless of POD24 status. Abstract presented at: European Hematology Association 2023 Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S222.
2. Jurczak W, Ghesquieres, Karimi Y, et al. Longer follow-up from the pivotal EPCORE NHL-1 trial reaffirms subcutaneous epcoritamab induces deep, durable complete remissions in patients with relapsed/refractory large B-cell lymphoma. Poster presented at: European Hematology Association 2023 Congress; June 8-11, 2023; Frankfurt, Germany. Poster P1118.
3. Genmab showcases data from comprehensive epcoritamab development program in patients across B-cell lymphomas at European Hematology Association (EHA) Annual Meeting 2023. News release. Genmab A/S. June 9, 2023. Accessed June 22, 2023. https://bit.ly/3XEhzs4
4. Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. J Clin Oncol. 2023;41(12):2238-2247. doi:10.1200/JCO.22.01725

Results Highlight Ropeginterferon Alfa-2b’s Potential

Results for ropeginterferon alfa-2b-njft (Besremi; PharmaEssentia) were presented at the 2023 European Hematology Association (EHA) Congress, which was held in June in Frankfurt, Germany. The subcutaneous therapy, a next-generation monopegylated interferon alfa-2b, has approval from the FDA and the European Medicines Agency for treatment of adults with polycythemia vera (PV), a rare a cancer that starts with diseased stem cells that can cause an increase of red blood cells, white blood cells, and platelets.1

PV can trigger cardiovascular conditions such as thrombosis or embolism, or it can transform to myelofibrosis or leukemia. The potential for ropeginterferon alfa-2b to address these secondary conditions and effects of prior treatment was the focus of data presented at EHA.

In the first abstract, which was the basis of an oral presentation by Harinder “Harry” Gill, MBBS, MD, FRCP, FRCPath, FHKCP, a clinical associate professor at Hong Kong University School of Clinical Medicine, investigators explained the risks faced by patients with primary myelofibrosis (PMF).2 Even if they begin at low or intermediate-1 risk based on the Dynamic International Prognostic Scoring System (DIPSS), patients are likely to progress to higher risk levels or overt MF, the authors noted. “There is currently no consensus on the optimal treatment for these patients,” they wrote.2

Efficacy in Myelofibrosis
Gill presented phase 2 results involving 62 patients with confirmed pre-PMF, overt PMF, post PV-MF, or post–essential thrombocythemia MF (PET-MF). Patients had to have DIPSS low or intermediate-1 risk levels and the need for cytoreduction.

Patients received ropeginterferon alfa-2b at the starting dose of 250 mcg followed by 350 mcg at week 2 and 500 mcg every 2 weeks from week 4 onward. The primary outcome was hematologic responses, which were assessed at 24 and 48 weeks. Secondary outcomes included adverse events (AEs), changes in measurements of gene mutations, quality of life, cytokine profiles, and an evaluation of bone marrow for cancer biomarkers.2

Data cutoff was February 27, 2023. The 62 patients (36 men, 26 women) had a median age of 59 years (range, 30-86). Among this group, 44 patients were pre-PMF (71%), 6 had overt PMF (9.7%), 5 had PPV-MF (8.1%), and 7 had PET-MF (11.3%).2

More than two-thirds (69.4%) had JAK2V617F driver genes (n = 43); other driver genes were CALR mutations (type 1/type 1–like) seen in 13 patients, type 2/type 2–like seen in 4 patients, and MPL mutation seen in 1 patient. According to the abstract, next-generation sequencing of nondriver mutations showed high molecular risk mutations among 8 patients (12.9%).2

The median time from diagnosis to treatment was 5 months, with a range from 1 month to 22 years. Baseline measures were as follows2:

  • median white blood cell count (WBC), 7 × 109/L (range, 3.3-33.95);
  • hemoglobin, 12.6 g/dL (range, 7.1-15.9);
  • platelet count, 500 × 109/L (range, 113-1114); and
  • lactate dehydrogenase, 277 IU/L (range, 136-1146).

The baseline median Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score was 16 (range, 0-49). Despite the study parameters of follow-up at 24 and 48 weeks, the median follow-up was 55 weeks (range, 9-61), with 56 patients (90%) and 35 patients (56%) having completed 24 and 48 weeks of treatment, respectively.2

Responses. At the 24-week mark, responses in hemoglobin (defined as 10g/dL to upper limit normal) at the 24-week mark were 76.6%; in WBC (WBC < 10 × 109/L), 87.2%; and in platelet (defined as platelet count ≤ 400 × 109/L), 78.7%.2

In addition, 36 of 39 evaluated patients with JAK2V617F mutations (92%) had stable or improved JAK2V617F allele burden, as measured by droplet digital polymerase reaction. Three patients (8%) had a greater than 50% reduction in the JAK2V617F allele burden, and 1 patient achieved undetectable JAK2V617F starting at week 16.2

Three patients stopped treatment, including 2 for personal reasons; 1 had symptoms progress. One case of pre-PMF progressed to overt PMF. No cases in the study progressed to blast phase.2

The most common AEs were malaise, reported by 29 patients (47%), with all but 1 case at grade 1 or 2; 26 (42%) patients had anemia, all but 4 were at grade 1 or 2; 23 patients (37%) reported hair loss, all at grades 1 or 2; 8 patients (13%) had thyroid problems without symptoms. No neuropsychiatric or autoimmune disorders were seen.2

Investigators concluded that ropeginterferon alfa-2b “was generally well-tolerated, effective in cytoreduction, and induced molecular responses early in JAK2V617F-mutated patients with pre-PMF and low/intermediate-1 risk PMF.”2

Effective Regardless of Prior Hydroxyurea Use. Another abstract evaluated patients treated with ropeginterferon alfa-2b for PV based on their prior treatment with hydroxyurea (HU), which the authors said “has been widely used as one of the myelosuppressive agents of first choice” for PV.3 Although use of HU can reduce thrombosis risk, this treatment can be associated with cytopenia and suboptimal hematological control over time, as well as leg ulcers and canker sores, they noted. In addition, the authors said, there is “concern for the second primary malignancy.”3

Now that phase 3 data have shown that ropeginterferon alfa-2b produces more durable hematological and molecular remissions than HU,4 the investigators sought to examine data that might show any clinical efficacy and safety differences for patients receiving ropeginterferon alfa-2b based on prior exposure to HU.

Investigators enrolled 99 patients from 16 hospitals in Korea. Eligible patients were 19 years or older with PV diagnosed based upon World Health Organization 2016 criteria, requiring cytoreductive therapy and having hematocrit of at least 45%.

Patients received ropeginterferon alfa-2b subcutaneously every 2 weeks, starting with a dose of 250 mcg, followed by 350 mcg at week 2, 500 mcg at week 4 and thereafter until week 48. The quantitative JAK2V617F allele burden was assessed every 3 months. HU resistance and intolerance were defined based on the modified European Leukemia Net criteria.

Results. Data cutoff was February 3, 2023. A total of 95 patients could be evaluated for the full data set, including 52 who were HU-naïve (54.7%) and 42 (45.3%) who were HU resistant or intolerant (R/I). Investigators reported no differences in baseline characteristics between the 2 groups. Prior to the cutoff date, 93 patients were evaluable at 3 months, 77 at 6 months, 48 at 9 months, and 28 at 12 months after starting therapy. Investigators reported:

  • During dose escalation, 4 patients (4.5%, 4/88) could not receive 500 mcg due to adverse events (AEs), but no serious AEs were reported.
  • Mean hematocrit at baseline was 50.25% ± 5.11%, which decreased to 41.15% ± 6.05% at 12 months. A statistical difference was found between the HU-naïve patients and those with HU R/I until 36 weeks of treatment, but hematocrit was controlled below 45% after week 36 regardless of subgroup.
  • Complete hematologic response (CHR) was seen in 25 (27%) of 93 patients at 3 months; in 35 (45%) at 6 months, in 31 (65%) at 9 months, and in 18 (64%) at 12 months. CHR at 48 weeks was seen in 11 (65%) of the 17 HU-naïve and 7 (64%) of the HU R/I patients.
  • In an evaluation of patterns for JAK2V17F allele burden changes, rapid decreases were seen in HU-naïve patients relative to the HU R/I patients.

“Our data demonstrated that ropeginterferon alfa-2b therapy, with rapid dose optimization, induced hematological response, reduced JAK2V17F allele burden, and was well tolerated in Korean patients,” the investigators wrote.

Compared with HU-naïve patients, those with HU resistance or intolerance “showed a delayed CHR response, but not much difference in after 36 weeks of treatment. These results suggest that ropeginterferon alfa-2b is an effective treatment option for PV regardless of prior HU therapy,” they concluded. 

1. U.S. FDA approves Besremi (ropeginterferon alfa-2b-njft) as the only interferon for adults with polycythemia vera. News release. PharmaEssentia. November 12, 2021. Accessed July 7, 2023. https://bit.ly/3D0LsZW
2. Gill H, Au L, Tsai D, et al. Efficacy and safety of ropeginterferon alfa-2b for pre-fibrotic primary myelofibrosis and DIPSS low/intermediate-1 risk myelofibrosis: updated results and genomic characteristics. Presented at: European Hematology Association 2023 Congress; June 8-11, 2023; Frankfurt, Germany. https://bit.ly/43yffns
3. Lee SE, Yoon SS, Yang DH, et al. Comparison of the response to ropeginterferon alfa-2b in hydroxyurea-naïve versus resistance/intolerance polycythemia vera: the Korean single-arm open-label multicenter study. Presented at: European Hematology Association 2023 Congress; June 8-11, 2023; Frankfurt, Germany. https://bit.ly/44OEvah
4. Gisslinger H, Klade C, Georgiev P, et al; PROUD-PV Study Group. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4

Related Videos
Dr Mrinal Gounder
Related Content
© 2023 MJH Life Sciences
All rights reserved.