AUDIO JOURNAL OF ONCOLOGY—Ibrutinib Enables Transplant-Free Therapy for Mantle Cell Lymphoma

Audio Journal of Oncology Podcast

Ibrutinib Enables Transplant-Free Therapy for Mantle Cell Lymphoma

NEW ORLEANS, USA—Many patients eligible for autologous stem cell transplantation for their mantle cell lymphoma (under current best practice recommendations) could be treated as effectively—and potentially with less toxicity—with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, according to findings from Munich, Germany.

The Randomized Triangle Trial, conducted by the European Mantle Cell Lymphoma Network, reported positive findings about a transplant-free approach to the American Society of Hematology 2022 Annual Meeting.

https://ashpublications.org/blood/article/140/Supplement%201/1/490022/Efficacy-and-Safety-of-Ibrutinib-Combined-with

Audio Journal of Oncology correspondent Peter Goodwin talked with study leader Martin Dreyling MD PhD, Professor of Medicine at LMU (Ludwig Maximilian University) Hospital in Munich, Germany about their findings that strongly suggest standard chemotherapy plus ibrutinib (with or without autologous stem cell transplantation) should be the new first-line standard of care for patients with mantle cell lymphoma.

Toxicity

But the German team also noted that the high efficacy of chemotherapy brought high toxicity rates. So, they compared the standard induction (with a cytarabine-containing regimen plus autologous transplant and rituximab maintenance) with two experimental arms, said Dreyling. “One was a simple add-on design—which means ibrutinib [was] added to [standard] induction and maintenance. And the third arm was even more interesting: substituting for autologous transplant.”

“The add-on design resulted in a significant improvement of progression free survival—around 15 per cent after three years: in my opinion highly clinically relevant,” he said. Also, the study found that a group of difficult-to-treat patients—those whose tumors had p53 gene alterations—had specifically benefited from the addition of ibrutinib.

Patients who took the targeted drug ibrutinib had rates of failure-free survival (FFS) and overall survival (OS) that were similar to the current standard of care—whether or not they received a stem cell transplant in addition to ibrutinib. Those treated with ibrutinib who did not have ASCT had significantly lower rates of toxicity. And in the arm in which ibrutinib was added to transplantation, the toxicity was no higher than among patients treated with standard of care, the study found.

“We are moving away from intensive chemotherapy to [a] targeted approach. The new standard of care in younger patients is still a combination of chemo plus ibrutinib. The future, I hope, will be skipping chemotherapy [altogether] and moving to a purely targeted approach—hopefully leading to better outcomes, but definitely better tolerability of our treatment regimens,” Dreyling told OT.

Study details

The trial enrolled 870 adult patients up to 65 (median age 57 years) treated for MCL in 13 European countries and Israel. All patients were eligible for ASCT. 288 of them (group A) were assigned to receive standard care (high-dose cytarabine-containing immunochemotherapy followed by ASCT and rituximab maintenance). 292 patients (group A + I) were treated with the same standard care plus ibrutinib, and 290 patients received ibrutinib without having a transplant (group I).

Transplant not superior

After a median follow-up of 31 months, group A failed to show superiority over group I in terms of FFS (three-year FFS was 72 per cent compared with 86 per cent in group I (p=0.9979, hazard ratio: 1.77). In group A+I, the FFS was superior to group A: 88 per cent compared with 72 per cent in group A (p=0.0008, hazard ratio: 0.52). OS was 86 per cent in group A, 91 per cent in group A+I, and 92 per cent in group I.

Toxicities

The study found no substantial differences in the incidence of grade three to five adverse events (AEs) during induction with R-CHOP/R-DHAP versus ibrutinib-R-CHOP/R-DHAP.

But during maintenance therapy there were substantially more grade three to five AEs in group A+I as compared either to group A or to group I. Neutropenia, leukopenia, febrile neutropenia, infections and cardiac disorders were all increased—many doubled in incidence—suggesting that ibrutinib may be best used as a replacement for stem cell transplantation rather than an addition.

“We have to wait for the full results,” said Dreyling. “So far, we don’t see any difference between [the] two ibrutinib curves for progression-free survival and overall survival. But already both curves are numerically superior to the old standard, autologous transplant only. I think clinicians will interpret these results as suggesting you may essentially substitute autologous transplant with ibrutinib to avoid its well-known long-term toxicities,” he said.

“From the perspective of toxicity, the ideal regimen is a combination of conventional chemotherapy plus ibrutinib,” said Dreyling.

His reasoning for reaching this conclusion was that not only had failure free survival improved when ibrutinib had been added to standard transplant therapy but the removal of transplantation altogether had proved highly beneficial.

Avoiding transplantation

The head-to-head comparison of ibrutinib versus ASCT had been even more interesting, he said, because skipping autologous transplant significantly reduced toxicity—which is what the study found. “When we started, we said autologous transplant had to be superior to remain the standard of care. However, to our surprise, what we observed was a flip-around of the curve. In fact, the ibrutinib arm was superior to autologous transplant.”

Overall survival

Although the statistical analysis had not yet be completed, both of the ibrutinib-containing arms of the study resulted in numerically superior overall survival. “That somewhat confirms that the life cycle of autologous transplant—in my opinion—is over and we now move on to the targeted approaches,” said Dreyling.

There was a big gain to be made for patients by skipping the acute toxicity of transplantation, Dreyling said. This was in the range of 60 per cent incidence of grade three to five myelosuppression and a 20 per cent infection rate caused by it. “This is totally skipped in the ibrutinib-only arm,” he said.

Quality of life

Dreyling said that from the doctor’s perspective ASCT was easy, but was not at all easy from the patient’s perspective. “We have a lot of patients with delayed reduction of general quality of life. And therefore, I think this is really an important step forward—besides all the late toxicities of autologous transplant we couldn’t yet analyze so far,” he said.

Dreyling pointed out emphatically that the study had been led and funded by academic institutions which he said was hugely important. “This study proves the role of academic trials—independently performed,” he said. Recruiting almost 900 patients with mantle cell lymphoma—also proved the value of international collaboration, he said.

ASH 2022 Annual Meeting

ABSTRACT 1: Efficacy and Safety of Ibrutinib Combined with Standard First-Line Treatment or As Substitute for Autologous Stem Cell Transplantation in Younger Patients with Mantle Cell Lymphoma: Results from the Randomized Triangle Trial By the European MCL Network

Program: General Sessions Session: Plenary Scientific Session Hematology Disease Topics & Pathways: Research, clinical trials, adult, Lymphomas, non-Hodgkin lymphoma, Non-Biological therapies, Clinical Research, B Cell lymphoma, Chemotherapy, Diseases, aggressive lymphoma, Therapies, Lymphoid Malignancies, young adult , Study Population, Human Sunday, December 11, 2022, 2:00 PM-4:00 PM

Martin Dreyling, MD1, Jeanette K. Doorduijn, MD, PhD2, Eva Gine, MD, PhD3, Mats Jerkeman, MD, PhD4, Jan Walewski, MD5, Martin Hutchings, MD, PhD6*, Ulrich Mey, MD7,8, Jon Riise, MD, PhD9*, Marek Trneny, MD10, Vibeke K.J. Vergote11*, Melania Celli12*, Ofer Shpilberg, MD, MPH13*, Maria Gomes da Silva14*, Sirpa Leppa, MD, PhD15, Linmiao Jiang16*, Christiane Pott17*, Wolfram Klapper, MD18*, Döndü Gözel1*, Christian Schmidt, MD1*, Michael Unterhalt, MD, PhD1*, Marco Ladetto, MD19 and Eva Hoster1,20*

1Department of Internal Medicine III, LMU University Hospital Munich, Munich, Germany 2Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands 3Department of Hematology, Hospital Clinic of Barcelona, IDIBAPS, CIBERONC, GELTAMO, Barcelona, Spain 4Division of Oncology, Skane University Hospital and Lund University, Lund, Sweden 5Department of Lymphoid Malignancies, Maria SkÅ‚odowska-Curie National Research Institute of Oncology, Warsaw, Poland 6Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark 7Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland 8Oncology and Hematology, Kantonsspital Graubünden, Chur, Switzerland 9Department of Oncology, Oslo University Hospital, Oslo, Norway 10First Department of Internal Medicine – Hematology, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic 11Department of Hematology, University Hospitals Leuven, Leuven, Belgium 12U.O. di Ematologia, Ospedale degli Infermi di Rimini, Rimini, Italy 13Institute of Hematology, Assuta Medical Centers, Tel-Aviv, Israel 14Department of Hematology, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal 15Department of Oncology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland 16Institute for Medical Information Processing, Biometry and Epidemiology (IBE), LMU University Munich, Munich, Germany 17Clinic for Internal Medicine II – Haematology, Oncology, University Clinic Schleswig-Holstein, Kiel, Germany 18Department of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Kiel, Germany 19Department of Translational Medicine, University of Eastern Piedmont and Az Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy 20Institute for Medical Information Processing, Biometry and Epidemiology, LMU Munich, Munich, Germany

On behalf of the European MCL Network

ML and EH contributed equally

Introduction: High-dose cytarabine-containing immunochemotherapy followed by autologous stem cell transplantation (ASCT) and rituximab maintenance represents the current standard of care for younger mantle cell lymphoma (MCL) patients. The BTK-inhibitor ibrutinib has shown promising efficacy in relapsed (Dreyling et al, Hemasphere 2022) and previously untreated older MCL patients (Wang et al., NEJM 2022). In 2016, the European MCL Network initiated the randomized, open-label, 3-arm TRIANGLE trial to evaluate the addition of ibrutinib to standard treatment (arm A+I) in comparison to the previous standard treatment (arm A) and an ibrutinib containing treatment without ASCT (arm I).

Patients and methods: Patients with previously untreated, advanced stage II-IV MCL, up to 65 years and suitable for high-dose cytarabine and ASCT were randomized 1:1:1 to the 3 trial arms A, A+I, and I in 13 European countries and Israel. Study treatment consisted of 3 cycles R-CHOP/R-DHAP without (arm A) or with ibrutinib added to R-CHOP cycles and 2 years maintenance (arms A+I, I). ASCT was planned for responding patients of arms A and A+I. Rituximab maintenance could be applied according to national guidelines in all responding patients irrespective of the trial arm. For the primary outcome, failure-free survival (FFS), stable disease at the end of induction, any progression, or death were counted as events. Three pairwise log-rank tests for FFS were monitored with regular pre-planned interim analyses maintaining each a one-sided 0.0167 significance level. A pre-defined decision criterion based on the statistical significance of the treatment comparisons was established to determine the future treatment recommendation. Secondary outcomes were overall response (OR), complete remission (CR), overall survival (OS), and grade 3-5 AEs.

Results: Between July 2016 and December 2020, 870 patients were randomized to A (n=288), A+I (n=292), and I (n=290). Median age was 57 years (range 27-68), 76% of the patients were male, 87% had stage IV, and 58%/27%/15% had low/intermediate/high risk MIPI. OR and CR rates were 94% and 36% of 272 evaluable patients in arm A (R-CHOP/R-DHAP) as compared to 98% and 45% of 559 evaluable patients in the combined A+I/I arms (ibrutinib-R-CHOP/R-DHAP). After a median follow-up of 31 months, A failed to show superiority over I in terms of FFS with 3-year FFS 72% (A) vs. 86% (I; p=0.9979, hazard ratio: 1.77, Figure 1A). A+I was superior to A in terms of FFS with 3-year FFS 88% (A+I) vs. 72% (A; p=0.0008, hazard ratio: 0.52). Subgroup analyses by the intention to apply rituximab maintenance did not change the main results on the lack of superiority of A vs. I and the superiority of A+I vs. A . Statistical monitoring for the FFS comparison of A+I vs. I is still ongoing. Three-year OS was 86% in A, 91% in A+I, and 92% in I (Figure 1B). There were no substantial differences in the occurrence of grade 3-5 AEs during induction with R-CHOP/R-DHAP vs ibrutinib-R-CHOP/R-DHAP (neutropenia: 47%/49% of patients, leukopenia: 15%/15%, febrile neutropenia: 9%/12%, infections and infestations: 9%/12%, cardiac disorders: 2%/3%). The two ASCT-containing arms did not substantially differ in grade 3-5 AEs (A/A+I: neutropenia: 36%/33%, febrile neutropenia: 20%/22%, leukopenia: 17%/17%, infections and infestations: 17%/20%). In contrast, during maintenance, there were substantially more grade 3-5 AEs in A+I as compared to A and I (A+I/A/I: neutropenia: 44%/17%/23%, leukopenia: 4%/2%/2%, febrile neutropenia: 6%/3%/3%, infections and infestations: 25%/13%/19%, cardiac disorders: 3%/1%/4%).

Conclusions: The addition of ibrutinib during induction and as maintenance with or without ASCT showed strong efficacy with acceptable toxicity. It has been clearly demonstrated that the current standard high-dose regimen is not superior to the new ibrutinib-containing regimen without ASCT. More follow-up is needed to clarify the role of ASCT in the context of ibrutinib-containing treatment. However, the current results already support the use of ibrutinib in the first-line treatment of younger MCL patients.