Tweet Chat Recap: Evaluating Treatment Approaches for Relapsed/Refractory DLBCL

Kami J. Maddocks, MD

Targeted Oncology was joined by Kami J. Maddocks, MD, associate professor of clinical internal medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center–James, for the discussion of a 76-year-old man with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in a recent tweet chat. In this case scenario, the patient presented with stage IV high-risk disease and received R-CHOP (Rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone), and radiotherapy.

Although the treatment appeared well-tolerated, the patient presented with similar symptoms as at diagnosis after completing 6 cycles with complete response to the therapy. According to the work-up, the patient is ineligible for transplant.

The patient was ineligible for stem cell transplantation (SCT), which Maddocks speculates may be due to the patient’s age, although other considerations could include comorbidities or intolerance to R-CHOP. Eligibility is the first thing she considers for her patients as it is currently the standard of care and the only curative approach for patients to receive salvage chemotherapy followed by consolidation with autologous SCT.

Maddocks told Targeted Oncology, “In some patient cases, [the reason for ineligibility] is age even though there's no specific age cutoff, but we know that it's harder on the marrow as patients get older to collect stem cells and get that aggressive salvage chemotherapy. Patient comorbidities [can also impact eligibility], so heart conditions, lung conditions, renal insufficiency can be a problem. Performance status and then lastly, just if the patient had trouble getting to their initial chemotherapy with R-CHOP or had a lot of complications, then it's probably going to be harder for them to tolerate even more aggressive or intensive therapy.”

In a twitter poll ahead of the chat, Targeted Oncology asked what the next best line of therapy for this patient might be, with 4 potential different treatment options. The option that drew the most attention, however, was the recently approved regimen of tafasitamab (Monjuvi) and lenalidomide (Revlimid).

Maddocks tweeted, “All these options are potential therapeutic choices for this patient, but the combination of tafasitamab/lenalidomide is the only option approved in this setting. The treatment has a promising ORR [overall response rate], and CR [complete response], and the remissions for patients who respond are durable!”

During the tweet chat, Maddocks reviewed each of the different treatment options in the poll, and why she selected this combination regimen as the next best line of therapy for this particular patient. Following the chat, she spoke with Targeted Oncology to share further insights on each of these therapeutic approaches and the importance of the FDA’s approval of tafasitamab plus lenalidomide in this setting.

Tafasitamab/Lenalidomide Draws Most Attention for Next Best Line

The combination of tafasitamab plus lenalidomide held the majority vote, which Maddocks agreed would be the next best line of therapy for this patient.

“For patients who are not candidates or considered eligible for a salvage chemotherapy followed by autologous SCT, the tafasitamab/lenalidomide combination was recently approved in the setting of first relapse, and it's the only approved therapy in this setting,” Maddocks said. “Historically, we would give some sort of palliative chemotherapy approach if patients were candidates and interested in pursuing therapy, or consideration of clinical trial, but this is the only therapy approved in this setting.”

The approval of tafasitamab in combination with lenalidomide includes an indication for patients who are not eligible for autologous SCT, as describes the patient in our case. This regimen was approved on the basis of the phase 2 L-MIND (NCT02399085) clinical trial, which explored this use of this regimen in 81 patients with relapsed/refractory DLBCL. Two-year follow-up demonstrated an ORR of 58.5%, which included CRs in 41.3% of patients and partial responses (PRs) in 17.5% of patients. In addition, 15.0% achieved stable disease, and the median duration of response was 34.6 months (95% CI, 26.1-34.6).¹

“I think this patient case is the perfect example of where this can fit into the treatment landscape,” Maddocks explained. “For patients who first relapse from the standard R-CHOP therapy, the toxicities were generally manageable, and with the response rate, this is a great option for patients at first relapse who are not going to be candidates for a transplant. I think maybe patients who go on to get palliative chemotherapy or maybe patients who get treatment with plans to go to transplant but just don't tolerate it and don’t look like they're going to [undergo] aggressive therapy, this may be an option for those patients too, understanding that there is some role for CAR T in a set of those patients.”

This study, which was presented during the 25th Congress of the European Hematology Association (EHA), demonstrated that the majority of toxicities were hematologic, and most were reversible. The most common grade ≥3 hematologic treatment-emergent adverse events (TEAEs) were neutropenia in 49.4% of patients, thrombocytopenia in 17.3%, and febrile neutropenia in 13.2%.¹

“These were able to be managed by holding the dose growth factor, and there was a population of patients who had to be dose-reduced on the lenalidomide. The starting dose was 25 mg, so the majority were able to maintain 20 mg if they were dose-reduced, although a few had to be reduced more than once,” Maddocks said. “The most common grade 3/4 or serious AEs were infection, probably not surprisingly, and overall, that's probably similar to what you see with other options in this setting. There was a small number of infusion reactions, but these were all grade 1 in the trial and were easily managed.”

Non-hematologic TEAEs of grade ≥3 included pneumonia in 8.6% of patients and hypokalemia in 6.2%. Serious AEs reported included pneumonia in 8.6%, febrile neutropenia in 6.2%, and pulmonary embolism in 3.7%, as well as bronchitis, lower respiratory tract infection, atrial fibrillation, and congestive cardiac failure in 2.5% each.¹

“Given the safety profile of this combination of tafasitamab plus lenalidomide, this regimen is particularly suitable for a large proportion of patients with DLBCL,” Gilles Salles, MD, PhD, lead author of L-MIND, told Targeted Oncology. “We do know that the median age of occurrence of DLBCL is in the late 60s, and there are many, many patients that are over 70 and that are not usually transplant eligible. Clearly this is a great opportunity for patients to receive this non-cytotoxic regimen.”

Although this regimen is an exciting opportunity for patients with DLBCL and relapsed/refractory disease, 1 challenge that needs to be addressed is the potential use of tafasitamab plus lenalidomide in sequence with CAR T-cell therapy. There is very little experience, if any, of patients receiving the combination regimen after receiving CAR T-cell therapy. The combination and CAR T cells both target the same antigen, CD19, which can be problematic. As it’s known that some patients will lose CD19 expression on CAR T-cell therapy, the regimen may no longer be an effective treatment option.

“For those patients that had failed CAR T-cell therapy, substantial proportions, about 30% of them, may have lost CD19 expression and then may not be eligible anymore for this regimen. There is, however, a substantial proportion of patients that retains CD19 and in whom tafasitamab/lenalidomide can be used as a treatment option,” Salles commented.

A large proportion of patients will maintain CD19 expression following CAR T-cell therapy, so tafasitamab plus lenalidomide may still be effective in a percentage of patients.

“It’s hard to say because we don’t have a lot of data, but we do know there are other CD19-directed therapies outside of CAR T cell development,” Maddocks told Targeted Oncology. “I think in the next few years, we’re going to see patients treated both pre- and post-CAR T with other CD19-directed therapies, and we’ll have more information on this.”

Polatuzumab Vedotin Combination May Be Promising Alternative

The combination of polatuzumab vedotin (Polivy) plus bendamustine (Bendeka) and rituximab (BR) was approved by the FDA as treatment of patients with relapsed/refractory DLBCL after 2 prior lines of therapy in June 2019 based on the findings from the phase 1b/2 GO29365 (NCT02257567) clinical trial. Although this option is also not FDA-approved for the treatment of patients after first relapse, Maddocks noted that this was the only treatment evaluated in a randomized trial. The study had included patients who were ineligible for transplant.

Significant improvements were observed with polatuzumab vedotin plus BR compared with BR alone in an international, multicenter, open-label study, particularly in regard to the ORR, CRs, progression-free survival (PFS), and overall survival (OS). CRs were observed in 40.0% of the patients with the combination versus 17.5% with BR alone. Survival rates favored the combination as well, with a median PFS of 9.5 months with the combination versus 3.7 months with BR alone (HR, 0.36; 95% CI, 0.21-0.63; P <.001) and a median OS of 12.4 months versus 4.7 months (HR, 0.42; 95% CI, 0.24-0.75; P =.002), respectively.²

“The addition of polatuzumab did increase toxicity from the standpoint of cytopenias, but that didn't really translate to increased serious infections. It did add neuropathy as a side effect, but most of that was reversible, so I think this was a regimen that, by the addition of polatuzumab, was something that you could offer patients that did give them somewhat of a better overall response and was more durable than just giving them a palliative chemotherapy alone,” Maddocks added. “This is also a regimen that's been used in patients who were not able to achieve a remission to bridge them to CAR T or in some patients after CAR T, and so I can understand why this was definitely one of the more favorable choices.”

In the study, grade 3/4 neutropenia was observed more frequently in the combination arm (42.6%) compared with the BR alone arm (33.3%), but the occurrence of grade 3/4 infections was comparable between the 2 groups (23.1% vs. 20.5%, respectively). In addition, the study authors noted that although many of the fatal AEs occurred after disease progression, 11 patients in the BR arm experienced fatal AEs compared with 9 in the combination arm, infection being the most common, which was the cause in 4 patients in each arm.²

Although the regimen appeared tolerable in this setting, Maddocks tweeted, “it is more attractive than chemotherapy alone and understandable why it was chosen [as the second-best option in the Twitter poll].”

Remaining Treatment Options Offer More Hope in Third Line & Beyond

Among the treatment options considered in our twitter poll ahead of the tweet chat, selinexor (Xpovio) only caught the attention of 16.7% of voters, similar to CAR T-cell therapy. However, both of these options are currently only approved in patients who have received at least 2 prior lines of therapy, which this case did not.

In regard to selinexor in particular, Maddocks tweeted, “Looking at the single arm phase 2 data, it also has the lowest overall response rates of all the options listed with an ORR of 28%.”

Selinexor received its approval from the FDA in June 2020, which is indicated for the treatment of adult patients with relapsed/refractory DLBCL, not otherwise specified, who have received at least 2 prior systemic therapies. This is the only oral single-agent therapy approved in this setting, and it is also the only nuclear export inhibitor approved by the FDA for use in hematologic malignancies.

The agent was approved on the basis of the phase 2b SADAL clinical trial, which demonstrated an ORR of 29% with 13% CRs and 16% PRs. The responses achieved in the study were durable, which led to a median duration of response of 9.2 months in the overall population (95% CI, 4.8-23.0) and 13.5 months in those who had achieved a CR (95% CI, 9.3-23.0).³

The most common treatment-related AEs were cytopenias and gastrointestinal/constitutional symptoms, which were generally reversible and manageable with dose modifications and/or standard supportive care approaches. The most common on-hematologic AEs, which were mostly grade 1/2, were nausea (52.8%), fatigue (37.8%), and anorexia (34.6%). The most common grade 3/4 AEs included thrombocytopenia (39.4%), neutropenia (20.5%), and anemia (13.4%). No treatment-related grade 5 AEs were observed.

CAR T-cell therapy, on the other hand, offers a unique option to this patient case even though it is still only approved in patients who have progressed or relapsed after 2 prior therapies or SCT. The TRANSCEND-PILOT-017006 (NCT03483103) study is evaluating the potential for CAR T-cell therapy lisocabtagene maraleucel (liso-cel) as treatment of patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma who have received at least 1 prior therapy and are ineligible for SCT. While this does appear promising for introducing CAR T-cell therapy earlier on for patients with DLBCL, the treatment is not available off trial and is not a standard approach.

Maddocks told Targeted Oncology, “It's very clear who's eligible for autologous transplant by age and comorbidities, but with CAR T, it's not so clear all the time who is going to be a candidate. There's not as great of data or information on who is going to be a candidate for that or not. Probably more patients are going to be a candidate for transplant, but there is still going to be patients that are comorbidities that they're not going to be a candidate for CAR T cells, and while they're approved in this setting and they can be very effective, there's also logistical issues, including that right now there's only certain centers, most often transplant centers, that are able to administer CAR T cells, so the patient has to have access to a center, they have to be able to get through the time that their leukapheresis cells are sent out and then sent back, and there's still barriers to cost and insurance in some patients, too.”

“This particular patient case does represent a challenge,” Maddocks said. “Historically, this is not a patient that's going to be a candidate for an autologous SCT, and that's going to be the only curative approach. CAR T is not approved in this setting, which is the other curative approach we know outside of patients who are unable to get to autologous STC, or at least appears to be likely curative for a percentage of patients.”

Overall, CAR T-cell therapy is not a viable treatment option for the patient depicted in our tweet chat discussion, although it can still offer curative opportunities to a select group of patients with DLBCL who are ineligible for transplant.

In conclusion, tafasitamab plus lenalidomide helps fulfill the unmet need of patients who are in first relapse but are ineligible for transplant, which is the only curative option for patients with relapsed/refractory DLBCL. Although CAR T cells appear hopeful in this space, more research needs to be done to further determine their role in the treatment paradigm.

“When you look at relapsed DLBCL, in general, and have these options, it's exciting for our patients to be able to have these. All of these have come up in the last 1 to 2 years, CAR T being a little bit longer than the other 3 regimens, but they all have offered patients tolerable therapy in the setting of previously not having these options.”

_Reference

_{1. Salles G, Duell J, González-Barca E, et al. Long-term outcomes from the phase II L-MIND study of Tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Presented at: Presented at: EHA25 Virtual; June 11-21, 2020. Abstract EP1201.}

_{2. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019;38(2):155-165. doi: 10.1200/JCO.19.00172}

_{3. Kalakonda N, Cavallo F, Follows G, et al. A phase 2b study of selinexor in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). Hematol Oncol. 2019;37(S2). doi: 10.1002/hon.31_2629}