During a Targeted Oncology Case-Based Roundtable event, Jakub Svoboda, MD, discussed the case of a 75-year-old patient with diffuse large b-cell lymphoma.
During a Targeted Oncology Case-Based Roundtable event, Jakub Svoboda, MD, associate professor of Medicine, Hospital of the University of Pennsylvania in Philadelphia, PA, discussed the case of a 75-year-old patient with diffuse large b-cell lymphoma (DLBCL).
Targeted OncologyTM: What are the approved treatment options for such a patient in the second-line setting? What disease characteristics would help to determine which regimen should be used?
SVOBODA: Once we would determine that the patient is not a candidate for transplant, the NCCN [National Comprehensive Cancer Network] guidelines [say that] the preferred regimens as of early 2021—the next meeting is in September, so we’ll have some other updates—are gemcitabine/oxaliplatin plus or minus rituximab [Rituxan] and polatuzumab vedotin [Polivy] plus or minus bendamustine plus or minus rituximab.1
The regimens [most oncologists are more] familiar with [include] dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] if the patient is not a transplant candidate in the second line—I’m not sure where that would be, and I’m not sure that people would use [this here]—and CEOP [cyclophosphamide, etoposide, vincristine, prednisone], which is basically etoposide instead of erythromycin. Some of the other regimens that are mentioned [in the guidelines are] gemcitabine-based regimens—the GDP [gemcitabine, dexamethasone, carboplatin] and gemcitabine/vinorelbine. Rituximab monotherapy in the [older] or very fragile patients [has a] 20% response rate; and tafasitamab [Monjuvi] plus lenalidomide [Revlimid] is now approved for second line for those patients who are not eligible for autologous stem cell transplant [ASCT].
DLBCL is pretty heterogeneous, so we have been trying to always determine [if it is the] germinal center B-cell [GCB] origin or the non–germinal center activated B-cell [ABC] type. And for the non–germinal center type, which [is] CD10 negative, it seems that ibrutinib [Imbruvica] works particularly well, so it’s sometimes used in these more fragile patients as a monotherapy.
What is different about the novel agent tafasitamab?
Tafasitamab has been approved now for several months in combination with lenalidomide for adult patients with relapsed or refractory DLBCL—this can include the patients with lymphoma that transforms from, let’s say, follicular or low-grade lymphoma and who are not eligible for ASCT.2
Tafasitamab is an antibody against CD19. For simplification purposes, you can think of [it as similar to rituximab] which is an anti-CD20 antibody, but this is an anti-CD19 monoclonal antibody. With rituximab or other monoclonal antibodies, the mechanism of action is binding the antibody to CD19-positive B cells, which causes direct cell death but also cell-mediated cytotoxicity and cellular phagocytosis.
Then I think the lenalidomide has synergy, in some ways, and potentiation of activity both in vivo and in vitro, and we know the lenalidomide can activate the T cells and natural killer cells. It can have activity alone, especially in the ABC subtype of DLBCL.
What data support the approval and use of this regimen in this setting?
So again, this is a combination. We know [that as a] single agent, tafasitamab may also have activity. It was fairly low activity in DLBCL, 25% or so, when it was studied as a monotherapy.3 But the interesting thing was that the patients who responded had a very nice, long duration of response [DOR] that lasted for quite some time. The median duration was around 20 months, so those were quite impressive data.
The study that was the basis for the FDA to approve tafasitamab with lenalidomide was a phase 2 study, single arm, open label [L-MIND trial; NCT02399085].4 It included about 80 patients with DLBCL. They were deemed not eligible for ASCT. Primary refractory patients were to be excluded initially, but some of the primary refractory patients got on the study.
Tafasitamab was given as an intravenous infusion, very similar to [rituximab], and it’s given weekly for the first 3 cycles for the first 3 months, with the asterisk [being] that, for the first cycle, they give the tafasitamab on day 1 and day 4—so, Monday and Thursday, then another Monday, and then just on Mondays. For cycles 4 [through] 12, you would give it only twice a month, on day 1 and day 15, and you give the lenalidomide in the typical multiple myeloma dose—25 mg per day, 3 weeks on, 1 week off.
This was done for a year for 12 cycles; and patients who had stable disease or better were allowed to continue on with tafasitamab maintenance, just twice a month, until progression. The primary end point was overall response; secondary end points were progression-free survival [PFS], DOR, safety, and biomarker analysis.
The 81 patients who were enrolled [had a] median age of 72, the majority had stage III or IV disease [75%], and the median [number of] prior lines of therapy was 2. They did sneak in some primary refractory patients, about 19%; those were the patients who didn’t respond to their frontline [therapy]. There were also a few patients who had prior stem cell transplant. When you look at the GCB versus non-GCB [subtype], the majority were patients who were difficult to determine [67%], but it looked [like for patients for whom] we have the data, more had the non- GCB than the GCB [subtype]. The data [we have show that] the older the patients get, the more likely they are [to have] the non-GCB subtype.
What did the study findings show?
Response was pretty excellent for this situation. Again, this is in patients who are progressing after R-CHOP and are not candidates for transplant. There was a 43% complete response [CR] rate. I like the updated data from the 2-year follow-up, where the median DOR is 34 months. That’s pretty good—3 years.5 There was partial response in 14 patients, or 17%; stable disease, 15%; progressive\ disease, 16%; not evaluable, 10%. The disease control rate was 74%. The Kaplan-Meier curves [for] DOR after 24 months of follow-up [show] pretty long durations, especially in the CR group, and so it looks like a good agent in that setting.
When you look at PFS rate at 1 year, it’s 50%. Median overall survival, which I think is quite important for this type of population, is 74% at 12 months and 18 months, 64%.4 With 2 years of follow-up, the median PFS was 16.2 months [and the] median overall survival was 31.6 months for all the patients.5
What was the safety profile like for the combination regimen?
The most common adverse events [AEs] were hematologic. I think that [the AEs are] not very different from the lenalidomide monotherapy. I’m not sure whether there is a great mechanical or physiologic reason why the cytopenias, other than lymphopenia, would be clearly affected by the CD19 antibody. There were no deaths and no grade 5 hematologic or nonhematologic toxicities on the L-MIND study. There were definitely neutropenias, thrombocytopenias, but the numbers were fairly low.
There were a few episodes of neutropenic fever; there was 1 patient with agranulocytosis. I’m not familiar with exactly what happened, but like with any treatment, you have to watch blood counts quite closely. Overall, the numbers look very good in terms of the AEs.
[For the] nonhematologic AEs, rashes we see with lenalidomide; diarrhea; fatigue—difficult to attribute to one or the other—but overall, it was a well-tolerated [regimen].
In these older patients, the serious AEs that were found to be treatment related by investigator were about 19% of the patients—15 out of 81. The serious AEs would [include] any hospitalization, for example, or longer [emergency department] visit, over 24 hours. These types of things happen over a year of active lymphoma. Twelve percent discontinued the combination due to AEs. So even though there were treatment-emergent AEs leading to death, that was defined by protocol. None were considered related to the study treatment, but they occurred during the treatment with this regimen. I’m not sure exactly what details, but 4 patients out of the 81 died while on the study.
The combination had many more AEs than the tafasitamab alone, which is understandable because the combination has lenalidomide, [which] can cause cytopenias, anemia, and all of these other issues that we discussed already. For the tafasitamab monotherapy, there have been some cases of cytopenias, but it’s hard to know whether it’s just carried over, to some extent, from the lenalidomide. You could think, like with [rituximab] maintenance, whether you could have some increased infections. There were 2 cases of febrile neutropenia, but overall [it was] well tolerated.
1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2021. Accessed May 12, 2021. https://bit.ly/3geoS5N
2. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed May 12, 2021. https://bit.ly/3bodb9v
3. Jurczak W, Zinzani PL, Hess G, et al. A phase IIa, open-label, multicenter study of single-agent tafasitamab (MOR208), an Fc-optimized anti-CD19 antibody, in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma: long-term follow-up, final analysis. Blood. 2019;134(suppl 1):4078. doi:10.1182/blood-2019-124297
4. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4
5. Salles G, Duell J, González Barca E, et al. Primary analysis results of the single arm phase II study of MOR208 plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (L-MIND). Abstract presented at: 15th International Conference on Malignant Lymphoma; June 18-23, 2019; Lugano, Switzerland. Accessed April 15, 2021. https://bit.ly/3wZgJIt