10 minutes reading time (1962 words)

Tafasitamab/Lenalidomide for Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Gilles Salles, MD, PhD

Gilles Salles, MD, PhD.

Recently, the FDA granted accelerated approval to tafasitamab-cxix (Monjuvi®, MorphoSys US Inc.) in combination with lenalidomide for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplantation. In this interview with i3 Health, Gilles Salles, MD, PhD, principal investigator of the phase 2 L-MIND trial, on which the approval was based, discusses the significance of the approval, adverse events of note with tafasitamab/lenalidomide, and important advances in the treatment of relapsed/refractory DLBCL.

What are the greatest challenges of treating transplant-ineligible patients with relapsed/refractory DLBCL?

Gilles Salles, MD, PhD: So when we address patients with relapsed/refractory DLBCL that are non–transplant eligible, we face different difficulties. The first one is that these are usually patients that are either elderly or have comorbid conditions, and they suffer from the disease and associated impairments linked to the disease. We have a couple of chemotherapy regimens that we are used to proposing to these patients, including bendamustine/rituximab, the recently approved bendamustine/rituximab combination with the new antibody-drug conjugate polatuzumab vedotin, as well as, for instance, rituximab in combination with gemcitabine/oxaliplatin, as our team-up regimens.

However, all of these regimens have their own toxicities, including hematological and infectious toxicities. Despite early results, we can achieve response in 30% to 50% of the patients, including some 20% to 40% with complete responses, but those responses are not lasting, so all of these treatments are essentially palliative treatments. There will always be small categories of patients that will survive and achieve a second remission and have long-term remission, but this is a very, very small minority of patients. So in offering the palliative treatment to someone who is 78, for instance, having them coming into the hospital for chemotherapy, we see neutropenia, we need to administer hematopoietic growth factors, they develop infections––I think it's a real burden for someone in order to prolong life expectancy for three to six months. It's worth it; we do it, but it has its limitations.

Can you comment on the significance of the approval of tafasitamab/lenalidomide in this population?

Dr. Salles: Tafasitamab/lenalidomide is a new combination that is not based on cytotoxic agents; it consists of what are basically immunomodulatory drugs. We have already known lenalidomide for many years because it is approved in multiple myeloma and has been approved for more than one year for patients with indolent lymphoma. Tafasitamab is an anti-CD19 antibody that has been engineered to enhance the activity of immune cells to kill tumor cells. The combination had had some promise in vitro. This is a phase 2 study that led to the approval, which was based on an overall response rate that reached 60% and a complete response rate of about 43%. I think that these results are really encouraging also because this combination offers a noncytotoxic regimen to patients. There is still some hematological toxicity, which we'll discuss later, but it's quite easy to manage. Lenalidomide is an old drug, and tafasitamab is a monoclonal antibody that needs to be infused intravenously, but it's great: what has been really impressive with the result of the study was the fact that patients responding to this combination had really prolonged response.

The median progression-free survival is more than one year, and the duration of response for responding patients is more than 18 months, so we really have the hope with this approval that we can offer our patients a regimen that is tolerable and that achieves a higher rate of response, a higher rate of complete response, and most specifically, a higher rate of very durable complete response, which has allowed our patients to come back to normal life with disease control. I think it's a great hope for patients.

What adverse events are of particular concern with tafasitamab/lenalidomide, and how should they be managed?

Dr. Salles: Tafasitamab/lenalidomide is an immune-based combination. We already know the side effects of lenalidomide; as I mentioned, it's an old drug that may present reversible, low-grade rashes for a few patients. A few patients present with gastrointestinal (GI) symptoms, as well as low-grade fatigue. Again, this is manageable, but there is some hematological toxicity that is different from the toxicity you encounter with chemotherapy: neutropenia, a little bit of anemia, and thrombocytopenia, which are usually reversible and quite manageable. There are very few patients that present with febrile neutropenia, which we see more often with chemotherapy. So there is a limitation with these side effects. Actually, most of the grade 3/4 side effects are hematological but again are easily manageable and reversible, and they don't present a severe burden for the patient.

We had an estimate recently for our presentation at the European Hematology Association showing that neutropenia occurs at a rate of 1.1 episode per year per patient, so it's not a major deal that will happen after every cycle of therapy. Thrombocytopenia occurs at a rate of 0.2 or 0.3 per year, so it's rather infrequent. So yes, there are a few hematological events linked to lenalidomide and to the combination, but overall it is quite manageable. We'll probably need to assess the quality of life of these patients, but I think from the patients I have seen, it's very well tolerated in general.

What additional research is being done on tafasitamab/lenalidomide in this population?

Dr. Salles: We have several ongoing investigations, some coming from the studies that already exist. We are looking for criteria that may reveal the characteristics of patients that have had more benefit from this combination, including initial characteristics, tumor burden, biology of the tumor, and also immune biology: whether the immune cells that present in the blood, such as natural killer (NK) cells, for instance, were predictive of response. So we can probably select the patients that may have more benefit and try to improve with other strategies for the patients that may not have had such great benefits from this combination. Other research will probably be to try to move this combination up front or move it earlier in the treatment of patients with diffuse large B-cell lymphoma. This can be done in two ways.

One is by combining this regimen with the classical rituximab/CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy, which is a standard chemotherapy regimen given to patients with diffuse large B-cell lymphoma. A phase 1 study has started investigating this combination.

Another way is to try to offer this combination in patients that are really elderly or have significant comorbidities, for whom we don't want to give a chemotherapy regimen or it's very difficult to propose a chemotherapy regimen. Maybe we have to evaluate whether or not this could be an option, even the tolerability of this regimen and the efficacy in patients that are not candidates for chemotherapy. So I think this is an interesting line of research.

A third way is that tafasitamab is being evaluated in combination with bendamustine in relapsed/refractory diffuse large B-cell lymphoma and compared to rituximab combined with bendamustine, which is ongoing and probably will bring results. Obviously now, with the approval of the drug, we do hope that many other studies will be carried on to better understand the efficacy and how to position this regimen in the management of patients with diffuse large B-cell lymphoma.

There is one additional point that should be made regarding tafasitamab/lenalidomide: tafasitamab targets the CD19 antigen on tumor cells, and this is the same antigen that is targeted by chimeric antigen receptor (CAR) T cells, which represent a very active treatment approved for DLBCL in the third line of therapy. So there is a theoretical concern, which is whether or not exposing patients to tafasitamab may eventually diminish the expression of CD19 and eventually prevent the efficacy of CAR T-cell therapy. There is nothing that has been demonstrated in this field, and I will say that there have been one or two patients already who have received CAR T after tafasitamab, but this is an area we need to investigate in order to help to position this combination in the armamentarium of patients with relapsed DLBCL.

Regarding all the advances, I think this regimen really helps us to understand that immune manipulation in patients with DLBCL is a very promising way to continue to make progress.

Are there any other research advances that look promising in relapsed/refractory DLBCL?

Dr. Salles: We had already made progress with CAR T-cell therapies and the different CAR T cells that are already in use or their combination with other immune-modulating agents. Obviously, this new combination of tafasitamab/lenalidomide is easier to use because it is off the shelf. We can re-add rituximab or another anti-CD20 antibody with this combination to see if it's more effective. One of the great areas of excitement we have right now is what are called bispecific antibodies, antibodies that recognize either CD19 or CD20 on the tumor cells and CD3 on T cells and bring those cells together in order to activate cytotoxic T cells. Early results with this family of bispecific antibodies appear really promising also.

What advice can you offer to hematologist-oncologists and other members of the cancer care team as they aim to optimize outcomes for transplant-ineligible patients with relapsed/refractory DLBCL?

Dr. Salles: First of all, when there is a clinical trial, try to offer the clinical trial to patients because this is the best way to access new drugs and evaluate their efficacy and safety.

I think that physicians will have to evaluate this combination of tafasitamab/lenalidomide in the patients they see in their own practice and see how it works. They need to carefully evaluate the different options with the patients that are not eligible for transplant––tafasitamab/lenalidomide, CAR T-cell therapy (which is another immune-based approach), and polatuzumab vedotin––and see what is the better approach for each patient. Discuss the pros and cons of every strategy, and make the appropriate choice in discussion with the patient.

About Dr. Salles

Gilles Salles, MD, PhD, has recently been appointed as the Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York. Previously, he served as Head of the Department of Hematology at the Lyon University Hospitals, Hôpital Lyon-Sud, in Pierre-Bénite, France. Dr. Salles's research has focused on the clinical and biological study of lymphoma. He has led investigations of T-cell and B-cell lymphoma experimental models and of genomics of indolent lymphomas, as well as identifying and validating new prognostic factors in patients with lymphoma. He has been involved in the development of new targeted therapies, monoclonal antibodies, and other immunotherapies. Dr. Salles has authored over 300 publications. Previously, he served as Chair of the Lymphoma Study Association. He is a member of several international societies, including the American Society of Hematology.

For More Information

Salles G, Duell J, González Barca E, et al (2020). Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol, 21(7):978-988. DOI:10.1016/S1470-2045(20)30225-4

Duell J, Maddocks K, González Barca E, et al (2020). Update of the single-arm phase II L-MIND study of MOR208 plus lenalidomide in relapsed/refractory diffuse large B-cell lymphoma: high overall response rates in patient subgroups with poor prognosis [poster presentation]. EHA24 Digital Congress. Abstract PF296.

Clinicaltrials.gov (2020). Phase Ib study to assess safety and preliminary efficacy of tafasitamab or tafasitamab plus lenalidomide in addition to R-CHOP in patients with newly diagnosed DLBCL. NLM identifier: NCT04134936.

Clinicaltrials.gov (2020). A trial to evaluate the efficacy and safety of tafasitamab with bendamustine (BEN) versus rituximab (RTX) with BEN in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (B-MIND). NLM identifier: NCT02763319.

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.

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