Obinutuzumab and the LyMa-101 trial – Expert discussion

This article is based on a webinar organized by the International Academy for Clinical Hematology (IACH) that focused on the paper recently published in The Lancet Haematology, entitled ‘Molecular response after obinutuzumab plus high-dose cytarabine induction for transplant-eligible patients with untreated mantle cell lymphoma (LyMa-101): a phase 2 trial of the LYSA group.’¹ Mohamad Mohty, Hôpital Saint-Antoine and Sorbonne Université, Paris, FR, chaired the session. He was joined by Christian Gisselbrecht, Hôpital Saint-Louis, Paris, FR, and first author of the study, Steven Le Gouill, Université de Nantes, Nantes, FR.

Obinutuzumab is an anti-CD20 monoclonal antibody that has demonstrated promising single-agent efficacy in patients with mantle cell lymphoma (MCL). The LyMa-101 study aimed to determine the value of obinutuzumab in combination with dexamethasone, high-dose cytarabine, and cisplatin (DHAP) in the MCL setting.² The Lymphoma Hub recently provided a summary of the results from the LyMa-101 study: access it here to complement the following article.

LyMa-101

Mohamad Mohty opened with a brief introduction to the study, which is summarized below:

• Open-label, single-arm, phase II trial (NCT02896582) evaluating obinutuzumab plus DHAP for transplant-eligible, untreated patients with MCL
• Treatment involved:
  • Four cycles of obinutuzumab + DHAP induction
  • Autologous stem cell transplant (auto-SCT)
  • Three years of obinutuzumab maintenance
  • Post-maintenance with obinutuzumab on demand for patients with measurable residual disease (MRD) positivity
• Primary endpoint: MRD negativity in the bone marrow (BM) following four cycles of obinutuzumab + DHAP
  • The study also compared the value of MRD measured in the BM vs peripheral blood (PB)

Background

Mohty then kicked off the discussion with the following question: What is the standard of care (SoC) induction today for young and fit patients with MCL who are eligible for intensive chemotherapy?

The consensus amongst the panelists was that high-dose cytarabine-containing regimens are the standard procedure prior to transplant in the MCL setting. Maintenance with rituximab is the subsequent step in the current SoC for these patients.

Discussion

Response assessment

The first major point of discussion was the primary endpoint of the study, and Mohamad Mohty questioned the benefit of PB/BM MRD assessment over positron electron topography (PET) scan. In response, Steven Le Gouill highlighted the ongoing importance of PET scan in lymphoma and emphasized that one should not replace the other, but rather the techniques should be used in conjunction to optimize patient prognosis. In contrast to other lymphoma entities, there is insufficient evidence surrounding PET scan to drive medical decisions in the MCL setting, Le Gouill argued.

BM assessment is an invasive diagnostic approach, and the LyMa-101 study sought to determine whether MRD negativity in the PB is an appropriate alternative. BM MRD negativity, however, is particularly difficult to achieve and remains the more stringent criteria for primary endpoint. At the 62^nd American Society of Hematology (ASH) Annual Meeting and Exposition, Mary Callanan presented an oral abstract (#120) on the LyMa-MRD project, which explored the predictive value of MRD assessment in the PB and BM of patients with MCL who were enrolled on the LyMa trial. In this presentation, she concluded that both BM and PB MRD status prior to auto-SCT are predictive of PFS and OS in younger patients with MCL, and that rituximab maintenance following auto-SCT resulted in prolonged PFS and OS, irrespective of MRD status. In alignment with the statement made by Steven Le Gouill, Mary Callanan suggested that the combination of PET scan and molecular MRD analysis strengthens the power of either alone as prognostic techniques.³

Importantly, the LyMa-101 study assessed BM MRD in the entire intention-to-treat population, not solely in those patients completing the treatment course. It therefore becomes unlikely that MRD negativity was overestimated in the participants of this study, and Steven Le Gouill proclaimed that this approach should be the standard across MCL clinical trials. Intriguingly, the only patient to experience disease progression had achieved MRD negativity in both the BM and PB, yet none of the 12 patients who displayed MRD positivity had relapsed by the 15-month follow-up. To understand this fully, Steven Le Gouill highlighted the need for a longer follow-up to determine progression-free survival in patients treated with the novel regimen. Regardless, data from this study provide the foundation for the use of obinutuzumab in the MCL setting as well as further exploration in alternative lymphoma entities.

Obinutuzumab vs rituximab

Another area of interest was whether obinutuzumab may be superior to rituximab in the indolent lymphoma setting. As pointed out by Steven Le Gouill, the LyMa-101 trial represents the largest series of patients with MCL to be treated with obinutuzumab. The data have shown that obinutuzumab can be added to the DHAP regimen to produce a favorable molecular response, while posing no greater toxicity than rituximab. The study does not, however, make efficacy comparisons to rituximab and therefore superiority of either agent cannot be determined. Le Gouill concluded this matter by highlighting the planned comparison of the LyMa vs LyMa-101 trials due to take place within the next 2 years.

The future and beyond

Mohamad Mohty next questioned the panelists on what they believe to be the most promising chemotherapy-free regimen for patients with MCL.

Christian Gisselbrecht pointed out that there are several encouraging ongoing phase II trials currently evaluating chemotherapy-free treatment options for MCL and that the ideal regimen would demonstrate high levels of MRD negativity. Steven Le Gouill expanded, suggesting a triplet regimen comprised of a Bruton’s tyrosine kinase inhibitor, a Bcl2 inhibitor, and an anti-CD20 monoclonal antibody. As an example, during the 2020 European Hematology Association (EHA) Annual Congress, Le Gouill presented data from Cohort C of the OAsis phase I/II study (NCT02558816), investigating the safety and efficacy of ibrutinib, venetoclax plus obinutuzumab in patients with newly diagnosed MCL. The triplet demonstrated encouraging tolerability and clinical efficacy: read a summary of the key results here.

It was considered that multi-arm studies comparing novel regimens to SoC chemotherapy will be imperative if the treatment landscape of MCL is to become chemotherapy-free. For example, the phase II ENRICH trial, evaluating rituximab + ibrutinib vs rituximab + chemotherapy (CHOP or bendamustine) as first-line treatment for patients with MCL, was predicted to be a major influencer on the SoC for MCL.

Conclusion

The phase II LyMa-101 trial has shown that obinutuzumab plus DHAP induction is efficacious and tolerated in transplant-eligible patients with untreated MCL. Nonetheless, a common theme of this discussion was the need for a longer follow-up and comparative trials to determine its benefit over current SoC. Mohamad Mohty concluded this exciting discussion with the below statement.