Hello, my name is Dr Gilles Salle. I’m a physician at the Memorial Sloan Kettering Cancer Center in New York, United States, and today I will discuss a 74-year-old patient who has been recently diagnosed with diffuse large B-cell lymphoma.

As I mentioned, this 74-year-old patient came to the clinic with a fever presenting for a couple of weeks. He had lost about 14 pounds, unintentionally, and had occasional chest pain in the axillary region. The previous medical history was diabetes mellitus, which was medically controlled, and on physical examination, he looked quite tired—this was the weight loss and a fever of a couple of weeks. He also had obvious palpable bilateral cervical lymph nodes that were not that big.

We started the clinical work-up of this patient. The LDH [lactate dehydrogenase] levels were elevated about 2-fold from normal values, hemoglobin level was slightly diminished to 10.8 g/dL, but everything was within normal range, and there was a slight elevation of creatinine value. Besides that, the other laboratory tests were within normal range.

The serological tests for hepatitis B and C, as well as HIV, were negative. The lymph node biopsy confirmed the large cells, which were CD20-positive, confirming the diagnosis of diffuse large B-cell lymphoma. Complementary examination with immunohistochemistry showed CD10-positive and CD19-positive on the report.

The patient went for a whole-body PET [positron emission tomography]-CT [computed tomography], and as a result, this exam showed activity on the cervical lymph node regions. The largest node was not big, about 2.5 cm, but he had evidence in other areas, such as the axillary region and thorax. He had some subcutaneous tissue involvement, which, because they were distant from the initial localization, classified this patient as stage IV. The performance status was 1, but this was a patient over 60 years old, with inoperable stage IV disease and elevated LDH, so he is in the high-risk category of patients.

What was decided for this patient was rather standard. The patient underwent immunochemotherapy with rituximab and CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] and it was well tolerated. He went through 4 cycles. The physician had the impression that the lymph nodes had not fully disappeared after 4 cycles, so an additional PET was prescribed after the 4 cycles. Unfortunately, what was seen on this new PET-CT was progression of disease. Given the age and the comorbidities, and the wish of the patient, the patient was deemed transplant ineligible, and the physician’s decision was to start this patient with tafasitamab and lenalidomide.

Presentation of a Patient With Diffuse Large B-Cell Lymphoma

 We are facing a patient with newly diagnosed diffuse large B-cell lymphoma. Despite being in good shape, this patient is 74 years old, an age where we are at a frontier between different treatment options. What was really important was that the work-up was done and this was a patient with inoperable stage IV disease, elevated LDH [lactate dehydrogenase] levels. He had these symptoms and was classified as a patient at high-risk in terms of the IPI [International Prognostic Index] classification. If we know the patient's prognosis, we know that given the age and the clinical characteristics of the patient, he may not be the optimal patient to be cured with frontline rituximab/CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]. There may be, unfortunately, a more substantial proportion of patients at this age and with these characteristics who either failed primary treatment or eventually have a relapse after achieving a clinical response.

It has been recommended in the WHO [World Health Organization] classification for patients with newly diagnosed diffuse large B-cell lymphoma that the cell of origin be analyzed by further molecular testing. This patient was CD10-positive, which already made him germinal center B-cell [GCB] type, but I advise to do this molecular testing because it helps to adjust treatment options at the time of relapse and at prognosis. We know that patients who are non-GCB have worse outcomes than those who are GCB.

Continuing with this patient, who is 74 years old, has diabetes mellitus, and clinical deterioration of the stages. Rituximab/CHOP remains the standard of care for these patients. He's GCB so there is no reason to choose any others. We don't have information about BCL2 but I think rituximab/CHOP will be the standard of care for this patient. I would have chosen 6 courses of R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] for this patient.

Typically, more than 80% of the patients respond to R-CHOP and a majority of them have achieved a complete response. A few achieved a partial response, and only about 10% of patients or a bit more at this age and with these characteristics will, unfortunately, fail to respond to R-CHOP. This was an unusual case because most patients will respond, but our physician’s attention was brought to the fact that the lymph nodes were still visible after 4 cycles. There is no routine interim PET [positron emission tomography] that needs to be performed, but when the patient has clinical evidence of disease after 3 or 4 cycles of R-CHOP, that is not normal, and we should do additional work-up for this patient, and that is what was done.

The patients who are refractory are rather rare, 5%-10%. With these clinical characteristics I will say that the percentage of patients who will relapse after achieving a response will be in the range of 30%-40%. That's quite a number of patients that we will have to deal with in terms of new treatment options at the time of relapse or refractory disease.

When we see a patient with diffuse large B-cell lymphoma who has a relapse, the first question we ask is, “Is this patient transplant eligible?” This is taken into account, considering age, comorbidities, and eventually the patient’s wishes, the place where he/she lives, and his/her environment. Here we have seen a patient who we felt was not transplant eligible because of his age and status, so for patients ineligible for transplant, the options are rather limited.

What we usually do is deliver another set of immunochemotherapy, including rituximab and different drugs. It could be either gemcitabine/oxaliplatin, this would be our GEMOX [gemcitabine/oxaliplatin] regimen. Or it could be bendamustine, and this will be the bendamustine/rituximab protocol. Recently, polatuzumab vedotin was approved as an option, but mostly for third-line treatment. For these patients who are transplant ineligible, these options usually carry a couple of adverse effects and difficulties being administered.

Initial Treatment of Diffuse Large B-Cell Lymphoma

 Recently we have new options available for patients with relapsed or refractory diffuse large B-cell lymphoma [DLBCL] since the FDA approved the combination of tafasitamab and lenalidomide for relapsed/refractory diffuse large B-cell lymphoma that is transplant ineligible. What is this combination? Tafasitamab is a CD19-directed antibody that has been engineered to improve the ADCC [antibody-dependent cellular cytotoxicity] and ADCP [antibody-dependent cellular phagocytosis] mechanisms of action. When engaging the antigen on the surface of the tumor cells, the modification of this antibody increases the ability of the immune cells to kill the tumor cells. Based on this rationale and on some experimental data, the combination of this antibody with lenalidomide was logical to test, given that we know that lenalidomide is able to increase the activities of some of the cytotoxic cells, such as NK [natural killer] cells.

The key study that led to the approval of tafasitamab and lenalidomide was called the L-MIND study. This was a phase 2, open-label study that enrolled patients who were transplant ineligible in the first or second line of relapse, with only a few patients who were actually refractory to first line. The primary end point was the overall response rate, and the overall response rate in the whole population reached 62%; in patients with true DLBCL it was 57%. The complete response rate was a total of 42.5%, and if you examine only the DLBCL it was 37%.

Reaching this kind of response rate with a regimen that is not chemotherapy-based but an immune-based regimen, is really encouraging. What we are seeing with this trial is that the progression-free survival was in a 12-month range, which is an important result for a second-line regimen in transplant-ineligible patients. Duration of response was really prolonged, and it was greater than 18 months on the last follow-up we had with the trial. If we specifically address the patients who have had a complete response to a combination of tafasitamab and lenalidomide, about 80% of these patients were still in response at 18 months.

I want to come back to the way this regimen is delivered. We have tafasitamab, which is infused initially weekly and then every 2 weeks. Lenalidomide is prescribed at the usual dose: 21 days, of 28. This is a combination that is given in 1 year. All patients have benefited from this kind of therapy with continuing tafasitamab as a single agent, 1 infusion every 2 weeks.

We recently updated the result of this trial, and the response rates that I described and the duration of response were confirmed with recent data. The median overall survival of these patients is in the range of close to 3 years, which is very encouraging for patients who are not transplant eligible.

I presented the data on the efficacy of this regimen in different categories of patients, and we found that there were no clear major differences in terms of patients who benefited from this combination. Patients who were treated at the time of first relapse or had the lower IPI [International Prognostic Index score], had a nonsignificant tendency to have a higher response rate. We have a few patients who were primary refractory who were not like this patient, but had an early failure just after completing R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone], and still a substantial number of them responded, as well as patients who were refractory to the second line of therapy. We had a few with transforming lymphoma who responded well, as well as response observed in patients with a higher tumor bulk.

Interestingly, lenalidomide has been described as active in patients with non-GCB [germinal center B-cell] tumors, so patients who have the genotype of activated B-cell but were characterized by immunohistochemistry; the combination is active for this patient but there is also good activity. This is seen in GCB-based patients, clearly underlying that the combination of tafasitamab and lenalidomide is really a synergy.

Results of the L-MIND Clinical Trial

When we deliver this treatment to this patient what are the main adverse effects that we see? The principle toxicity of this regimen is hematological, and this is linked to both agents, as single agents both have some hematological toxicity. About half of the patients experience grade 3 or 4 neutropenia, but only 10% of them develop infections, and when we looked at the number of neutropenic episodes during the first year of the study, it is about 1 episode per patient, so it's not a major burden, for instance, after chemotherapy.

There are also about 18%-20% of patients presenting with grades 3/4 thrombocytopenia. Over 1 year, it's probably 10%-15% of the patients who have such an event, and it's usually easily manageable. The other adverse effects that we see are commonly observed with lenalidomide: skin rashes that we can usually manage, GI [gastrointestinal] symptoms, or fatigue. You may want to adjust the dose of lenalidomide to improve the tolerability of this regimen. There were very few patients who had to quit the regimen because of adverse effects, especially very few adverse effects related directly to tafasitamab. So this is a quite well-tolerated regimen for patients who are not transplant eligible.

To further assess the efficacy of this regimen, the investigators also collected data on patients who were treated with lenalidomide alone. These are real-world data that were presented by my colleague Grzegorz Nowakowski, MD, at the recent ASCO [American Society of Clinical Oncology] meeting.

To better assess the value of the combination of tafasitamab and lenalidomide, investigators collected data on patients who were treated with lenalidomide alone as a single agent with diffuse large B-cell lymphoma in the relapsed/refractory setting. They collected hundreds of pieces of data, which were compared with what is called the match analysis. This is taking patients’ individual characteristics and comparing them with those patients who had received the L-MIND regimen in the study. What they found is that the overall response rate of the patients who received lenalidomide alone was 34%, with only 13% of them achieving a complete response, as opposed to the matched population of an overall response rate of 67% and a complete response rate of more than 44%. There was a marked difference in terms of overall response rate and complete response rate. When we looked at the progression-free survival [PFS], it was twice as long, exceeding or close to 12 months, with the combination of lenalidomide plus tafasitamab, as opposed to lenalidomide alone, which achieved a PFS of 6 months or less. These data were important and contributed to the ground of data on which the FDA approved the combination of tafasitamab and lenalidomide.

L-MIND Trial Regimen Overview

 There have been many new options for patients with diffuse large B-cell lymphoma [DLBCL] that have been available in the last few years. A major form of progress is the development of engineered T cells, also called CAR [chimeric antigen receptor] T cells. CAR T-cell therapy made a breakthrough 2 years ago showing that a patient with relapsed/refractory disease can achieve a substantial rate of response and complete response, and durable, complete response. However, the additional toxicities that are very specific to this treatment, such as the cytokine release syndrome, as well as the risk of neurological events, is a complicated process to put into treatment. We have to organize leukapheresis, we have to wait until the cells are manufactured, which may take a couple of weeks. We have to get insurance approval for these patients, so it is an efficient treatment, but it has also its constraints that can prevent the use in some patients.

Another recent approval was the antibody-drug conjugate against CD79, called polatuzumab vedotin, which was approved based on the randomized phase 2 study in combination with bendamustine/rituximab, achieving a 40% response rate, with the majority achieving a complete response and then a duration of response. This also represents an interesting option for our patients. There are also some hematological toxicity and infectious toxicity, as well as particular neurological toxicities that are linked to the toxin that is included in the antibody-drug conjugate, which appears to be well manageable and essentially of grade 1/2, but is obviously a spectrum of toxicity that is a little particular.

Finally, another drug was approved in the third-line treatment of diffuse large B-cell lymphoma, which is the first inhibitor of a molecule called XPO1. It is selinexor and this drug, which is an oral agent, can be delivered to the patient with some precautions regarding to fatigue, appetite, and other issues, but achieved a modest response rate. This is encouraging enough to allow the drug to be approved.

If we think about how we can choose a treatment and the different options, we first need to see whether the patient is right for the criteria of the approved drug. Chemotherapy plus rituximab combination will probably continue to be mainstream as a second option for patients, but with tafasitamab/lenalidomide, we may have an encouraging and interesting option for these patients. Probably more particularly for patients who have had some delay between the first treatment with R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] and a relapse after 1 year or more. Even then, we can use it in patients who are refractory and test it there.

One concern that was raised regarding the use of this combination and the use of CAR T-cell therapy are that both agents actually target the same CD19 antigen, bringing the hypothesis that exposing the cell to tafasitamab before the use of CAR T may eventually diminish or abolish the expression of CD19. In fact, we have no data to support that. There have been anecdotal reports of treatment as it has been exposed to tafasitamab with CAR T, but this is still a work in progress and we have to make sure that in thinking about the different sequencing of treatment, we don't oppose 1 treatment above the others. Unfortunately, we know that 1 patient at least who failed CAR T therapy has lost CD19 expression. So we have to think and discuss with the patient the different options and how we will sequence them: the classic immunochemotherapy, the availability of tafasitamab/lenalidomide, the CAR T cell, and eventually, the polatuzumab vedotin or selinexor.

We should have conversations with our patients regarding the different options that are available. Immune-based options, such as tafasitamab/lenalidomide. More complicated, but with marked efficacies, the CAR T cell is in third line until we get more data, and other combinations that are available with cytotoxic agents and targeted molecules. Having a good discussion with the patients and their relatives could help us to choose the optimal strategy to control relapsed/refractory DLBCL for each individual patient. Thank you for your attention.

A 74-Year-Old Man With Diffuse Large B-Cell Lymphoma

Presentation of a Patient With Diffuse Large B-Cell Lymphoma

Initial Treatment of Diffuse Large B-Cell Lymphoma

Results of the L-MIND Clinical Trial

L-MIND Trial Regimen Overview

Novel Treatment Options in Diffuse Large B-Cell Lymphoma