®: Could you provide some considerations for MOR208 as a second-line therapy in patients with diffuse large B-cell lymphoma (DLBCL) who have previously received a regimen that contains chemotherapy and rituximab? 

d-line therapies always begin with the goal. Patients with a curative approach generally receive a salvage chemotherapy such as RICE [rituximab, ifosfamide, carboplatin, and etoposide] and, if sensitive, an autologous peripheral blood stem cell transplant. But in some patients, that’s not a suitable goal; maybe their comorbidities are too high and prevent them from receiving such an aggressive approach, or maybe they’re a person in their late 70s or 80s where that’s not an approach. I think MOR208 combinations, such as with lenalidomide, are appropriate in that second-line setting. 

: Well, the MOR208 data are pretty impressive. The patient population with relapsed/refractory DLBCL is always difficult. These patients don’t have a ton of great treatment options, so we’re always interested in finding treatments that have high activity and good tolerability.

Tafasitamab [MOR208], a monoclonal antibody that targets CD19, and lenalidomide [Revlimid] can be given in combination. The lenalidomide is given for a year. The tafasitamab is given weekly for the first 3 months and then every other week, indefinitely. Overall, it looks to be a pretty well-tolerated regimen. The response rate was nice at 60%, with a complete response rate of around 40%. What was most impressive was the durability of those responses. Well over 50% of patients were still in remission at 18 months. 

: Results of the phase 2 L-MIND trial [NCT02399085] that combined MOR208 with lenalidomide, which included patients who were not eligible for stem cell transplant, showed a really promising overall response rate (ORR), 60%, and complete response rate, 40%. The median duration of response was about 21 months. To me, this seems to be really good activity of this combination in this population of patients with a significant unmet need. These patients actually have a poor prognosis, and at the same time this combination showed a reasonable adverse eveffect (AE) profile, and the toxicities were reasonable for such a regimen. I believe the infection rate was [about] 10%, with neutropenic fever rate of about 5%. It seems like most patients, about 70%, were able to be maintained on a dose of lenalidomide of more than 20 mg. Given all of that, I think it is a reasonable regimen to consider in the second-line setting in patients with relapsed or refractory DLBCL who are not eligible for stem cell transplant.

Would MOR208 be considered for those patients who are ineligible for chimeric antigen receptor (CAR) T-cell therapy and who are not candidates for polatuzumab? 

: MOR208 would be considered for anybody after relapse in DLBCL who is not suitable for a variety of other things. For instance, CAR T cells are a very aggressive treatment option; people need to be almost as fit as for a stem cell transplant to see CAR T cells. I don’t think it’s the same with patients receiving polatuzumab. Polatuzumab is given in combination with bendamustine and rituximab. Those patients have to have good hematologic function to be a candidate, and for some patients, that is not a realistic scenario. Perhaps they have cytopenias or they’ve received multiple chemotherapy before; getting more chemotherapy such as bendamustine and polatuzumab is not an appropriate approach. So MOR208 in combination with lenalidomide is a very appropriate treatment option for that group of patients. 

: If you’re treating patients with CAR T-cell therapy, you’re really still in a curative intent mindset, but many patients can’t make it to CAR T cell because they can’t get their disease under control. Some patients are just not appropriate for CAR T-cell therapy; others relapse after CAR T-cell therapy. All those patients would be appropriate for this combination of tafasitamab and lenalidomide. 

In that same space would be the polatuzumab vedotin plus bendamustine/rituximab combination that has FDA approval in relapsed/refractory DLBCL. That regimen hasn’t been compared head-to-head with the tafasitamab/lenalidomide combination, so it is hard to know how the 2 stack up against each other. Response rates look similar. The durability, on paper, perhaps looks a little better with [the] tafasitamab/ lenalidomide combination. For most patients, I do think the tafasitamab/lenalidomide combination would be better tolerated than a polatuzumab-based therapy. I could see a lot of investigators choosing the lenalidomide/tafasitamab as their regimen of choice for patients in this setting. 

: Yes, absolutely. I think it is a very reasonable option in this situation. I think obviously in this patient population there is something to be said about the AE profile, maintaining quality of life. If we’re look at patients who have relapsed or refractory DLBCL and are not eligible for transplant, that means we’re looking at patients who are older or who have comorbidities, and that’s where we need to have that balance between efficacy and a reasonable AE profile. That’s where I see a value in using this regimen. The other thing is that obviously lenalidomide is an oral drug and it is also not a chemotherapy, so that, too is of value for these patients.

Could you highlight some of the benefits of using a chemotherapy-free regimen such as MOR208? 

: I think chemo-free regimens are very popular with patients in general. We know from other diseases, such as chronic lymphocytic leukemia and low-grade lymphoma, that using these targeted agents that are chemo free are extremely popular. If you ask someone, “Would you rather receive a cytotoxic chemotherapy, or would you rather receive a targeted agent?” pretty much everyone chooses a targeted agent because you don’t have nearly as much off-target toxicity or as much collateral damage as you do with cytotoxic chemotherapy. [Avoiding] those adverse events (AEs) is an important treatment goal for many of my patients. 

From a patient perspective, do other benefits exist aside from the favorable toxicity profile of MOR208? 

: I think MOR208 [tafasitamab] is an attractive treatment option for many patients because it doesn’t have all the problems with cytopenias, or the nausea, vomiting, and all the [other] collateral damage that we see with cytotoxic chemotherapy. Giving it in combination with lenalidomide, which is an oral agent, is a benefit for many patients who are trying to avoid all the AEs that you see with traditional cytotoxic chemotherapy or even to a certain extent just with polatuzumab. Polatuzumab basically works like a targeted chemotherapy, so [by using MOR208] you’re avoiding some of the AEs you’d see with cytotoxic chemotherapy. 

: In general, a chemotherapy-free regimen tends to be better tolerated. That’s not always true, but often it is. One appealing part is [avoiding] the mechanism of action in which patients start exhibiting resistance to chemotherapy drugs. Often it doesn’t matter which other chemotherapy drugs you’d [change] to—they still have resistance, at least relative resistance. Even if they respond, the responses are pretty brief. So we’re always interested in finding agents that attack the cancer cells with a different mechanism, beyond the genotoxic damage of DNA-damaging chemotherapy. 

The appeal of lenalidomide/tafasitamab is that it’s trying to kill the cells in a fundamentally different way from a chemotherapy-based regimen, and it is generally more tolerable as well. 

: From the L-MIND study, it seems that MOR208 was very well tolerated. We would expect the AEs of monoclonal antibody–like allergic reactions, which probably showed up more in the patients after 12 cycles when lenalidomide was stopped, but otherwise it was well tolerated. We didn’t see significant toxicity in these patients after those 12 cycles, and we didn’t see a significant rate of infections.

In another study, the drug has shown promising activity as a single agent also, although my preference would be to use it in combination. But in a very frail patient, if I felt that they might not be even able to tolerate a combination, I might consider it as a single drug.

Say a patient has cycled rituximab after a drug holiday, with limited evidence of the efficacy of rituximab. Could MOR208 be considered next? Why or why not?

: We traditionally use rituximab in combination with chemotherapy because we don’t really know whether 

rituximab helps or not, but [we do know] that it probably doesn’t add much in the way of AEs. If you add it to yet another chemotherapy or another regimen, it [again] seems to add little in the way of AEs. [But] if you think about it, that’s not really the most rational approach, right? We don’t reuse other chemotherapy. We wouldn’t reuse adriamycin or [cyclophosphamide] or gemcitabine if someone was not responding to it anymore. We’re probably not adding all that much to chemotherapy or to regimens by continuing to use rituximab or other CD20 antibodies. Using other targeting antigens, such as CD19, or using MOR208, I think, is an attractive option for patients who’ve already been through treatment with another monoclonal antibody that targets CD20 or another target. 

: Certainly, most patients with relapsed DLBCL have been exposed to quite a bit of rituximab. It’s given in virtually every salvage chemotherapy regimen in combination, and a lot of patients have either absolute or relative rituximab resistance at that point. So going to a regimen that isn’t based on rituximab at all has a lot of appeal. Tafasitamab targets a different antigen, CD19 instead of CD20. So, again, the tafasitamab/lenalidomide combination [avoids] a strategy that patients have already been exposed to and has probably had diminishing returns at that point.

: Yes, I would consider it. It just makes sense, logically, to use a different drug that targets a different antibody rather than cycling the same drug we used before. In another trial, a phase 2 trial that looked at the use of rituximab and lenalidomide in patients with relapsed/refractory DLBCL, the ORR was somewhere around, I believe, 35% to 40%, so it doesn’t seem to me [to be] very different from the response rate to just [the] single agent [of] lenalidomide. That being said, obviously we’re not supposed to compare across trials, but I think somehow we cannot afford to not think about it.

Articles

Faculty debate the definitions of chemotherapy resistance, sensitivity, and refractoriness and discussed appropriate management strategies based on how patients would be classified in DLBCL.

Expert Perspectives in the Evolving Treatment Landscape of Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Recent trials of novel therapies and therapeutic combinations have introduced promising options for the management of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), including patients who are ineligible for or had disease progression after autologous stem cell transplant (ASCT). However, additional research is needed to elucidate the optimal candidates for each therapy and the best sequencing for the therapies, according to stakeholders who participated in a virtual 

, moderated by John Pagel, MD, PhD, of the Swedish Cancer Institute in Seattle, Washington.

Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone is the current frontline standard-of-care treatment for DLBCL and has been shown to cure almost 60% of cases in younger and elderly patients.

 However, effective treatment for the remaining patients with relapsed (appearance of a new lesion or ≥50% increase in size of previously involved sites after a complete response [CR]) or refractory (≥50% increase from nadir in the size of any abnormal lesion or appearance of a new lesion during or following initial treatment) disease remains a challenge.

The treatment strategy for a first relapse or primary refractory disease is guided by the eligibility of ASCT. Eligibility for ASCT depends on multiple factors, including medical fitness, presence of comorbidities, performance status, and patient preference, and Pagel noted that the “goalposts seem to be moving quite a bit.” 

M. Yair Levy, MD, of Texas Oncology in Dallas, said that salvage chemotherapy given at disease relapse is useful for conferring chemotherapy sensitivity and thereby predicting an optimal response to transplant. “If folks have early progression, which we usually define as less than a year, we know that their durability of response with ASCT is going to be suboptimal,” he said. “Also, if they don’t have a [CR] to treatment, we know that their results with ASCT are also going to be suboptimal. The folks whom we’d like to take to ASCT are usually the people who progressed [more than] a year [after initial chemotherapy] and achieve a [CR] to salvage chemotherapy.” Levy added that chimeric antigen receptor (CAR) T-cell therapy may be a better option for patients who do not respond to or relapse early with salvage chemotherapy.

Many options are available for salvage chemotherapy, with no clear evidence demonstrating superiority of one regimen over another. Alan Pierre Skarbnik, MD, of Novant Health in Charlotte, North Carolina, and his colleagues tend to prefer rituximab, ifosfamide, carboplatin, and etoposide (RICE), although he may consider a modified regimen of rituximab, dexamethasone, high-dose cytarabine, and cisplatin, which substitutes oxaliplatin for cisplatin, or a regimen of rituximab, gemcitabine, and oxaliplatin for patients unable to tolerate RICE. Although the stakeholders said that maintenance therapy is not useful for routine use in patients with R/R DLBCL, Charles M. Farber, MD, PhD, of Atlantic Health System in Morristown, New Jersey, said that he considers it for patients who need a bridging therapy when stem cell transplant or CAR T-cell therapy is delayed because of administrative issues.

The panelists also discussed the potential effects of the ongoing coronavirus disease 2019 pandemic on the diagnosis and treatment of patients with DLBCL. Ian Flinn, MD, PhD, of Tennessee Oncology in Nashville, said that although housing needs during treatment have had to be adjusted, as some facilities closed during the pandemic, treatment is generally not delayed or modified because of the emergent medical needs of patients with DLBCL. However, Skarbnik said that timely diagnosis of DLBCL is likely to be the primary issue moving forward, which could affect response to treatment.

“People are taking longer to go to the doctor [or] the emergency department,” Flinn said. “I’ve seen people presenting with a more extensive initial presentation in diffuse large cell lymphoma because…they took a longer time to go to the doctor than they have otherwise. We know for certain if patients delay treatment, they may respond less to chemotherapy, so I’m concerned that in the next several months, we’re going to see a surge of untreated disease because people had too much of a lag in initiating treatment.”

CAR T-cell therapy targeting CD19 has changed the treatment landscape for patients who have poor-risk DLBCL with no other treatment options that seem viable. Tisagenlecleucel and axicabtagene ciloleucel are the 2 CAR T-cell products currently approved for DLBCL based on data from the phase 2 JULIET and ZUMA-1 trials, respectively (NCT02445248, NCT02348216) showing CRs in approximately 40% of patients.

However, the panelists pointed out that access to CAR T-cell therapy remains a critical barrier for many patients. Skarbnik said that finding a center to receive CAR T-cell therapy and going through the insurance approval process also contribute to delays in receiving treatment. Shaker R. Dakhil, MD, FACP, of the Cancer Center of Kansas in Wichita, added that most of his patients require bridging therapy because it often takes 2 months to get the CAR T-cell therapy administered to the patient.

“By the time you talk to the patient and you get everything in flow, and then do all the testing, the PET scanning…by that time the disease is growing,” said Dakhil. “You have a refractory patient whose disease is galloping through that period.” 

However, results of a recent study using data from the US Lymphoma CAR T Consortium showed no statistically significant differences in progression-free survival (PFS), overall response rate (ORR), or CR rate (CRR) between bridging and nonbridging groups; results did show worsened overall survival (OS) in patients with DLBCL who received bridging therapy while waiting for treatment with axicabtagene ciloleucel, even after controlling for confounding factors.

 The investigators acknowledged that further studies are needed to clarify whether certain subgroups of patients may benefit and whether certain bridging strategies reduce efficacy of CAR T-cell therapy by changing the tumor microenvironment.

In the interchange, Skarbnik pointed out the importance of carefully selecting a bridging therapy that does not impair the ability to collect T cells for CAR T-cell therapy. “Radiation therapy is a fantastic bridge and approach [because it] increases tumor antigen presentation,” said Skarbnik. “[A patient] may become more immunogenic, and the CAR T cells may even improve their durability to attack those cells.”

Lenalidomide is an immunomodulatory agent that has demonstrated single-agent activity in R/R DLBCL. In a phase 2 trial testing lenalidomide in patients with R/R lymphomas, including DLBCL, the ORR was modest (28%) in the DLBCL population.

 However, lenalidomide with rituximab (commonly known as R

) has been shown to have synergistic antitumor effects in models of non-Hodgkin lymphoma, with enhancement of natural killer cell cytotoxicity, which introduced the rationale for using this nonchemotherapy combination in R/R DLBCL.

 A phase 2 trial evaluating efficacy of R2 in DLBCL, in transformed large cell lymphoma, and in grade 3 follicular lymphoma showed an ORR of 28% (9 of 32 patients). In the subset of patients with DLBCL, median PFS and OS were 2.8 months (95% CI, 1.8-11.1) and 10.2 months (95% CI, 6.6 to not reached), respectively.

 Common hematologic adverse events (AEs) included grade 3/4 neutropenia, thrombocytopenia, lymphopenia, and leukopenia, and common grade 1/2 nonhematologic AEs included fatigue, nausea, neuropathy, dizziness, myalgia, diarrhea, elevated lactate dehydrogenase levels, hyperglycemia, and hypoalbuminemia.

The stakeholders noted that the relatively limited duration of response, not the AE profile, is the main factor limiting their uptake of the regimen in their practices. Most said that they reserve R

 for palliative purposes in patients who are unlikely to tolerate high-dose chemotherapy.

Polatuzumab vedotin-piiq is a CD79b-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic agent that is delivered intracellularly and causes microtubule disruption and induction of cell death. Polatuzumab was recently approved for use in combination with bendamustine and rituximab in adult patients with R/R DLBCL after 2 or more prior therapies, based on results from the GO29365 trial (NCT02257567). The results showed a significantly higher CRR in patients who received the combination of polatuzumab, bendamustine, and rituximab than in those who received only bendamustine and rituximab (40% vs 17.5%; 

 PFS, OS, and duration of response after a median follow-up of 22.3 months were also significantly better in the group that received polatuzumab,

 although the stakeholders cautioned that the durability of response with the 3-drug combination was still somewhat limited.

Grade 3/4 anemia, neutropenia, and thrombocytopenia, as well as peripheral neuropathy, were more common in the group that received polatuzumab,

 although Skarbnik noted that removing bendamustine seems to improve tolerance in his experiences with off-label use for palliation. “These patients need to have some sort of quality of life,” he said. “I think the [bendamustine] really takes away from that.”

Most of the stakeholders said that they use the 3-drug combination, often with a reduced dose of bendamustine, for palliative purposes or as a bridging therapy to CAR T-cell therapy. Sai Ravi Pingali, MD, of Houston Methodist in Texas, said that although he was impressed that most of this difficult-to-treat patient population had a response to the 3-drug combination, the short duration of response is why he prefers using it as a bridging therapy for CAR T-cell therapy rather than for palliative purposes. However, Jose Sandoval-Sus, MD, of Moffitt Cancer Center/Memorial Healthcare System in Pembroke Pines, Florida, cautioned that in his experience, the prolonged cytopenias associated with bendamustine have increased the difficulty of obtaining adequate T cells for CAR T-cell therapy and has prompted his use of polatuzumab and rituximab without bendamustine.

Tafasitamab (formerly known as MOR208 or XmAb5574) is an Fc-engineered monoclonal antibody directed against CD19, which is broadly expressed in DLBCL and other B-cell malignancies. Targeting of CD19 by tafasitamab led to natural killer cell–mediated antibody-dependent cytotoxicity, phagocytosis, and apoptosis in several B-cell lymphoma cell lines.

 Results of a phase 2a trial showed that single-agent tafasitamab was clinically active in patients with R/R DLBCL, with an ORR of 26%, but the median duration of response was relatively modest (13.7 months) in patients with R/R DLBCL, prompting investigators to evaluate therapeutic combinations with tafasitamab.

Bendamustine, a non–cross-resistant alkylating agent, enhanced tafasitamab-mediated cytotoxicity in preclinical studies of lymphoma, which prompted investigators to study the combination of bendamustine and tafasitamab in patients with R/R DLBCL who are not eligible for high-dose chemotherapy and ASCT.

The ongoing phase 2/3 B-MIND trial (NCT02763319) is comparing tafasitamab and bendamustine with rituximab and bendamustine in patients with DLBCL who have relapsed or are refractory to up to 3 prior lines of therapy and are not candidates for high-dose chemotherapy and ASCT.

 In November 2019, the trial passed the preplanned, event-driven interim analysis for futility and recommended an increase in trial participants from 330 to 450, which was issued by an independent data monitoring committee (IDMC). This interim analysis involved an IDMC assessment of the data for the probability of a positive study at the primary completion of the study, with evaluations of efficacy data in the overall patient population and in a subgroup of patients with a low natural killer cell count at baseline.

However, the stakeholders were particularly enthusiastic about the recent data showing efficacy of the combination of tafasitamab and lenalidomide, which showed greater in vitro activity than either agent alone in a cell model of chronic lymphocytic leukemia, which expresses the B cell–specific CD19 antigen.

An observational, retrospective study compared a primary analysis of patients from the phase 2 L-MIND study (NCT02399085) of tafasitamab plus lenalidomide with a matched control cohort from the RE-MIND trial (NCT04150328) of lenalidomide alone. The combination of lenalidomide plus tafasitamab was associated with a superior ORR compared with lenalidomide alone (67.1% vs 34.2%, respectively; 

 < .0001) and with superiority across all secondary end points analyzed, including CRR (39.5% vs 11.8%).

The L-MIND trial was a single-arm study that included patients with R/R DLBCL who had received 1 to 3 prior systemic therapies (including at least 1 CD20-targeting regimen) and were ineligible for ASCT. Patients received twelve 28-day cycles of tafasitamab and lenalidomide, and after cycle 12, those who were progression free received tafasitamab every 2 weeks until disease progression.16 In the full analysis set (which included patients who received at least 1 treatment cycle), the ORR was 60.0% (48 of 80 patients) and the CRR was 42.5% (34 of 80).

 Prespecified patient subgroup analyses showed that the duration of response (DOR) rate at 12 months was similar regardless of the number of prior lines of therapy (70.5% for 1 prior line vs 72.7% for 2 or more prior lines).

 Additionally, the authors reported “encouraging outcomes” in patients with nongerminal center DLBCL determined by Hans algorithm, with an ORR of 71.4%, 12-month DOR rate of 83.1%, and 12-month OS rate of 84.2%.

 Two-year follow-up data (with a cutoff of November 30, 2019) were reported on May 14, 2020, and showed an ORR of 58.8% (47 of 80 patients) and a CRR of 41.3% (33 of 80) as assessed by an IDMC. The median DOR, median PFS, and median OS were 34.6 months, 16.2 months, and 31.6 months, respectively.

“These results are quite impressive,” said Flinn. “The patient population probably isn’t the same as what we’re seeing in some of the other studies…but a 60% ORR and high CRR are quite good.”

Common treatment-emergent AEs (TEAEs) reported in the preliminary results (data cutoff date of June 5, 2018) included neutropenia (48%), thrombocytopenia (32%), anemia (31%), diarrhea (30%), pyrexia (22%), and asthenia (20%), and 42% of patients required a reduction in their dose of lenalidomide.

However, Pagel noted that many of these AEs would likely show up with any agent used for these patients, and Haifaa Abdulhaq, MD, of the University of California, San Francisco, added that the cytopenias observed may have been related to lenalidomide because the patients who continued on tafasitamab alone after taking the combination for 1 year did not appear to have significant cytopenias. “Given the duration of response and the AE profile, this to me would be a really attractive option for this patient population if they are ineligible for transplant and CAR T-[cell therapy],” she said.

Although the results are preliminary, the stakeholders expressed optimism about the potential role for tafasitamab plus lenalidomide as a durable therapeutic option for patients with DLBCL. Dakhil pointed out that the relatively short median time to response could make it useful as a bridging therapy to CAR T-cell therapy.

Farber cautioned that integrating tafasitamab with CAR T-cell therapy may introduce issues related to targeting of CD19, as giving 2 different CD19-targeted therapies consecutively (eg, tafasitamab before or after CD19-targeted CAR T-cell therapy) may lead to loss of CD19 and thereby reduce the efficacy of tafasitamab.

Mosunetuzumab is a humanized immunoglobulin G1 bispecific antibody that targets CD3 and CD20 and redirects T cells to engage and eliminate B cells. Activation of T cells, elevation of cytokines, and increase in tumor-infiltrating lymphocytes were observed with mosunetuzumab in a biomarker analysis of patients enrolled in the phase 1/1b GO29781 trial (NCT02500407).

Unlike CAR T-cell therapy, mosunetuzumab does not require ex vivo T-cell manipulation and is thus available “off the shelf.”

GO29781 was a phase 1/1b dose-escalation and expansion study to evaluate mosunetuzumab in patients with R/R non-Hodgkin lymphoma, including some who had relapsed or were resistant to CAR T-cell therapy. Results of the dose-escalation part of the trial showed an ORR of 62.7% in patients with slow-growing disease and 37.1% in patients with aggressive disease. CRs were observed in 43.3% of patients with slow-growing disease and 19.4% of those with aggressive disease. Patients showed durable CRs, with 24 of 29 patients with slow-growing disease remaining in remission for up to 26 months off initial treatment and 17 of 24 patients with aggressive disease remaining in remission for up to 16 months. Patients who had received prior CAR T-cell therapy had an ORR and CRR of 38.9% and 22.2%, respectively, which Pagel pointed out were similar to the rates of response observed in patients who were refractory to anti-CD20 therapy.

Cytokine release syndrome, a hematologic AE, was observed in 28.9% of patients, whereas grade 3 neurological AEs occurred in 3.7%.

According to Pagel, the hematologic AEs tended to occur during the first cycle of treatment for the majority of patients. The therapy, he said, is associated with relatively low rates of infection and febrile neutropenia.

Overall, the stakeholders expressed optimism about the efficacy of this agent and the ability to give mosunetuzumab off the shelf without the need to harvest a patient’s T cells. However, they cautioned that longer follow-up data are needed on optimal dosing and therapeutic combinations that may be used with mosunetuzumab. “It’s definitely a very exciting agent [for an] extremely difficult population,” said Sandoval-Sus. “My only caveat is [that there has been] a very short follow-up.”

Selinexor is an oral selective inhibitor of XPO1, which is the major nuclear export protein for tumor suppressor proteins such as p53, IkB, and FOXO, as well as eIF4E-bound oncoprotein mRNAs such as c-Myc, Bcl-xL, and cyclins. Preclinical data showed that inhibition of XPO1 decreased protein expression of MYC, BCL2, and BCL6 through increased nuclear localization in triple-hit and double-hit DLBCL cell lines, and it prompted chemosensitization in doxorubicin-resistant DLBCL cells by reducing DNA damage repair mechanisms.

Selinexor recently received accelerated approval from the FDA for adult patients with R/R DLBCL not otherwise specified, including DLBCL as a result from follicular lymphoma, after 2 or more lines of systemic therapy.21 This approval was based on findings from the phase 2b SADAL trial (NCT02227251), which showed an ORR of 28.3% and CRs in 13 of the 127 evaluable patients. The authors also reported deep and durable responses in patients with germinal center or nongerminal center subtypes, with ORRs of 33.9% and 20.6%, respectively. Responses tended to occur rapidly, and the median duration of response was 9.2 months among responding patients.

Although the stakeholders acknowledged that the drug is active in a population that is notoriously difficult to treat, the toxicities associated with selinexor may limit widespread use. In the SADAL trial, 80% of patients developed gastrointestinal toxicity, 61% developed hyponatremia, and 25% experienced central neurologic AEs (including dizziness and changes in mental status).

 Although the investigators stated that most common TEAEs were generally manageable with dose modifications and standard supportive care,

 Sabarish Ayyappan, MD, of the Carver College of Medicine, University of Iowa Health Care, Iowa City, said that in his experience, cytopenias had tended to linger even after his patients stopped taking selinexor. Abdulhaq added that her patients with multiple myeloma, who receive an 80-mg dose of selinexor along with dexamethasone, often require significant dose reductions because of gastrointestinal toxicity and cytopenia. “Given that it’s being used in [DLBCL] as a single agent at 60 mg, hopefully it’s somewhat better tolerated,” she said. “It doesn’t seem like duration of response is very high, though, so it wouldn’t be a preferred option [for me].”

Sandoval-Sus added that ongoing studies looking at combinations that include lower doses of selinexor may help identify a less toxic and similarly effective dose, but he and Habte A. Yimer, MD, of Texas Oncology in Tyler, pointed out that it may not be the optimal choice for third-line therapy, which is a “very crowded” therapeutic space.

Loncastuximab tesirine is composed of a humanized antibody against CD19 that is stochastically conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. Binding of loncastuximab tesirine to the CD19 cell surface antigen leads to internalization of the antibody-drug conjugate, cleaving of the linker, and release of PBD dimers, which is followed by formation of cytotoxic DNA crosslinks, stalling of the DNA replication fork, and, ultimately, apoptosis of the cells.23 Results of a phase 2 study including 145 patients with R/R DLBCL showed that infusion of loncastuximab tesirine led to an ORR of 45.5%, including a CRR of 20%; all had been previously treated with 2 or more multiagent systemic therapies. The investigators reported “manageable” toxicity; the most common grade 3 or higher TEAEs included neutropenia, thrombocytopenia, and elevated γ-glutamyltransferase.

Although continued study in a larger group of patients is warranted, Farber stated that he sees it as another potential option for elderly patients who are not eligible for ASCT.

At the conclusion of the interchange, the stakeholders expressed optimism about the efficacy of several of the therapies for R/R DLBCL and emphasized that the next steps involve developing strategies for positioning these drugs and selecting therapeutic strategies based on patient characteristics and treatment goals. “Tafasitamab is the one that [is] exciting to me because it’s not as toxic, people tolerate [it, and] you have long-term remissions,” said Sandoval-Sus. “If the goal is to keep the patient alive with minimum toxicity, I think that’s a good drug to use.” 

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6. Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2011;22(7):1622-1627. doi:10.1093/annonc/mdq626

7. Wu L, Adams M, Carter T, et al. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res. 2008;14(14):4650-4657. doi:10.1158/1078-0432.CCR-07-4405

8. Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013;27(9):1902-1909. doi:10.1038/leu.2013.95

9. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172

10. Horton HM, Bernett MJ, Pong E, et al. Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. 

. 2008;68(19):8049-8057. doi:10.1158/0008-5472.CAN-08-2268

11. Jurczak W, Zinzani PL, Gaidano G, et al. Subgroup analyses of diffuse large B-cell lymphoma (DLBCL) and indolent lymphoma cohorts from a phase IIa study of single-agent MOR208 in patients with relapsed or refractory non-Hodgkin’s lymphoma (R-R NHL). J Clin Oncol. 2016;34(suppl 15):7545). doi:10.1200/JCO.2016.34.15_suppl.7545

12. Nowakowski GS, Belada D, Molina L, et al. B-MIND: MOR208 plus bendamustine (BEN) versus rituximab (RTX) plus BEN in patients with relapsed or refractory (R-R) diffuse large B-cell lymphoma (DLBCL): an open-label, randomized phase II/III trial. 

. 2017;35(suppl 15):TPS7571). doi:10.1200/JCO.2017.35.15_suppl.TPS7571

13. MorphoSys’ tafasitamab B-MIND DLBCL study successfully passed futility analysis. News release. MorphoSys. November 18, 2019. Accessed June 26, 2020. https://www.morphosys.com/media-investors/media-center/morphosys-tafasitamab-b-mind-dlbcl-study-successfully-passed-futility

14. Awan FT, Lapalombella R, Trotta R, et al. CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody. 

. 2010;115(6):1204-1213. doi:10.1182/ blood-2009-06-229039

15. MorphoSys AG: primary endpoint met in real-world data study demonstrating clinical superiority of the combination of tafasitamab and lenalidomide compared to lenalidomide alone. News release. MorphoSys. October 29, 2019. Accessed June 26, 2020. https://www.morphosys.com/media-investors/media-center/morphosys-ag-primary-endpoint-met-in-real-world-data-study

16. Duell J, Maddocks KJ, Gonz.lez-Barca E, et al. Subgroup analyses from L-Mind, a phase II study of tafasitamab (MOR208) combined with lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. 

. 2019;134(suppl 1):1582. doi:10.1182/blood-2019-122573

17. MorphoSys and Incyte announce long-term follow-up results from L-MIND study of tafasitamab in patients with r/r DLBCL. News release. Morpho-Sys. May 14, 2020. Accessed June 26, 2020. https://investor.incyte.com/news-releases/news-release-details/morphosys-and-incyte-announce-longterm-follow-results-l-mind

18. Salles GA, Duell J, Gonz.lez-Barca E, et al. Single-arm phase II study of MOR208 combined with lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma: L-Mind. Blood. 2018;132(suppl 1):227. doi:10.1182/blood-2018-99-113399

19. Roche announces new data on novel CD20-CD3 bispecific cancer immunotherapies in people with difficult-to-treat lymphomas. News release. Roche. December 7, 2019. Accessed June 26, 2020. https://www.roche.com/dam/jcr:054ac171-6fc7-4b73-8436-d31809849747/en/191207-irash-cd20-cd3-bispecific-en.pdf

20. Marullo R, Yang SN, Rashal T, et al. XPO1 is a rational target for double and triple-hit aggressive B-cell lymphomas. Cancer Res. 2015;75(suppl 15):LB-062). doi:10.1158/1538-7445.AM2015-LB-062

21. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. News release. FDA. June 22, 2020. Accessed June 28, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-relapsedrefractory-diffuse-large-b-cell-lymphoma

22. Karyopharm reports updated data from the phase 2b SADAL study at the 2019 International Conference on Malignant Lymphoma. News release. Karyopharm. June 19, 2019. Accessed June 28, 2020. https://investors.karyopharm.com/node/12071/pdf

23. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. 

. 2018;131(10):1094-1105. doi:10.1182/blood-2017-10-813493

24. ADC therapeutics announces positive results from pivotal phase 2 clinical trial of single agent loncastuximab tesirine (ADCT-402) in patients with relapsed or refractory diffuse large B-cell lymphoma. News release. ADC Therapeutics. January 9, 2020. Accessed June 28, 2020. https://www.globenewswire.com/news-release/2020/01/09/1968282/0/en/ADCTherapeutics-Announces-Positive-Results-from-Pivotal-Phase-2-Clinical-Trial-of-Single-Agent-Loncastuximab-Tesirine-ADCT-402-in-Patients-with-Relapsed-or-Refractory-Diffuse-Larg.html

: Since the Scientific Interchange Workshop that was held on May 29, 2020, described in this report, the FDA has approved Monjuvi (tafasitamab-cxix) in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Approval was granted on August 1, 2020. This is the first, and at this time is the only, FDA-approved, second-line treatment for adult patients with relapsed or refractory DLBCL who are ineligible for autologous stem cell transplant. Therefore, the opinions of the stakeholders who participated in this event were naive to the FDA approval of Monjuvi and its potential implications on the landscape of DLBCL treatment.

Recent trials of novel therapies and therapeutic combinations have introduced promising options for the management of patients with relapsed or refractory
diffuse large B-cell lymphoma.

Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Haifaa Abdulhaq, MD, an associate clinical professor in Hematology and Oncology at the University of California, San Francisco (UCSF) and the director of hematology and the Hematology/Oncology Fellowship Program at UCSF Fresno, discusses the benefits of chemotherapy-free options in diffuse large B-cell lymphoma (DLBCL).

There is something to be said about the safety profile of tafasitamab and how it helps patients maintain quality of life, says Abdulhaq. Patients who have relapsed/refractory DLBCL and are transplant ineligible, are often older or have comorbidities. In this patient population, maintaining a balance between efficacy and a reasonable toxicity profile is essential, according to Abdulhaql; this is a benefit provided with tafasitamab. Lenalidomide (Revlimid) is another important chemotherapy-free, oral agent that provides value to these patients, concludes Abdulhaq.

Videos

Haifaa Abdulhaq, MD, discusses the benefits of chemotherapy-free options in diffuse large B-cell lymphoma.

Dr. Abdulhaq on the Benefits of Chemotherapy-Free Options in DLBCL

Brad S. Kahl, MD, a medical oncologist at Siteman Cancer Center and a professor of medicine in the Division of Oncology at Washington University School of Medicine in St. Louis, discusses the utility of tafasitamab (MOR208, formerly Xmab®5574) combined with lenalidomide (Revlimid) in patients with diffuse large B-cell lymphoma (DLBCL) who are ineligible for CAR T-cell therapy.

If a patient is being treated with CAR T-cell therapy, they are being treated in a curative mindset, according to Kahl. However, many patients cannot receive CAR T-cell therapy because their disease is not under control, adds Kahl. Other patients are not appropriate for CAR T-cell therapy and some patients relapse after treatment with this modality. All these patients would be appropriate for the combination of tafasitamab and lenalidomide, says Kahl.

Polatuzumab vedotin (Polivy) in combination with bendamustine and rituximab (Rituxan) received regulatory approval from the FDA and is also used in relapsed/refractory DLBCL. These 2 regimens have not been examined head-to-head, which makes it difficult to know how they compare with one another, says Kahl. However, the response rates observed with these regimens appear to be similar.

With regard to durability, tafasitamab/lenalidomide might be a bit better on paper, adds Kahl; the combination would also be better tolerated by most patients versus a polatuzumab-based therapy. For those reasons, it is possible that many investigators would opt for the tafasitamab/lenalidomide combination as their regimen of choice for patients in this setting, concludes Kahl.

Brad S. Kahl, MD, discusses the utility of tafasitamab combined with lenalidomide in patients with diffuse large B-cell lymphoma who are ineligible for CAR T-cell therapy.

Dr. Kahl on the Utility of Tafasitamab/Lenalidomide in DLBCL

Ian W. Flinn, MD, PhD, director of lymphoma research and a principal investigator at Sarah Cannon Research Institute and director of the Sarah Cannon Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center, discusses the opportunity for second-line tafasitamab (MOR208, formerly Xmab

5574) as a palliative treatment of patients with diffuse large B-cell lymphoma (DLBCL).

The decision about which second-line therapy to use always begins with identifying the goal of treatment, says Flinn. In patients who have relapsed after standard frontline chemotherapy, such as the combination of rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone in DLBCL, a decision must be made on whether it will be a curative or palliative approach.

Patients who are given a curative approach would generally receive salvage chemotherapy, such as rituximab in combination with ifosfamide, carboplatin, and etoposide, and if they are sensitive to this therapy, then they go on to receive an autologous stem cell transplant. However, there is a group of patients where that is not an appropriate goal. For example, patients who are older with many comorbidities may not be able to receive such an aggressive approach. Tafasitamab in combination with other agents, such as lenalidomide (Revlimid), is appropriate if the goal for treatment is palliative rather than a curative in the second-line setting, concludes Flinn.

Ian W. Flinn, MD, PhD, discusses the opportunity for second-line tafasitamab (MOR208, formerly Xmab®5574) as a palliative treatment of patients with diffuse large B-cell lymphoma.

Dr. Flinn on Opportunities for Second-Line Tafasitamab in DLBCL

Haifaa Abdulhaq, MD, an associate professor in the School of Medicine of the University of California, San Francisco (UCSF); the director of hematology and the director of the Hematology/Oncology fellowship program at UCSF Fresno, discusses the safety profile of tafasitamab (MOR208) in diffuse large B-cell lymphoma (DLBCL).

The phase 2 L-MIND study enrolled patients with relapsed/refractory DLBCL who are not eligible for autologous stem cell transplant. Patients were treated with the combination of tafasitamaband lenalidomide (Revlimid). Data from that study show that the combination was well tolerated, says Abdulhaq.

Adverse events are expected with a monoclonal antibody, such as allergic reactions, but otherwise, it was well tolerated, and those events usually occur in patients after 12 cycles when lenalidomide was stopped, adds Abdulhaq. Investigators did not see significant toxicity or rates of infection after those 12 cycles.

In another study, tafasitamab had also shown promising activity as a single agent. Although, it is typically preferred to use the agent in combination with chemotherapy, because it has shown promise as a single agent, the monotherapy can be considered for a frail patient with DLBCL who might not be able to tolerate a combination therapy, concludes Abdulhaq.

Haifaa Abdulhaq, MD, discusses the safety profile of tafasitamab (MOR208) in diffuse large B-cell lymphoma.

Dr. Abdulhaq on the Safety Profile of Tafasitamab in DLBCL

Brad S. Kahl, MD, a medical oncologist at Siteman Cancer Center and a professor of medicine in the Division of Oncology at Washington University School of Medicine in St. Louis, discusses findings from the phase 2 L-MIND study in diffuse large B-cell lymphoma (DLBCL).

The monoclonal antibody tafasitamab (MOR208), which targets CD19, and lenalidomide (Revlimid) is a promising treatment option for patients with relapsed/refractory DLBCL, says Kahl. In the L-MIND study, lenalidomide was given for a year and tafasitamab was given weekly for the first 3 months and then every other week, indefinitely.

Overall, it appears to be a well-tolerated regimen with a high response rate of 60% and a complete response rate of 42%. The most impressive result was the durability of those responses, says Kahl.The majority of patients were still in remission at 18 months.

As such, if a patient is being treated with palliative intent and is no longer considered for curative intention therapies, such as autologous stem cell transplant or CAR T-cell therapy, the tafasitamab regimen is a fantastic option for those patients, concludes Kahl.

Brad S. Kahl, MD, discusses findings from the phase 2 L-MIND study in diffuse large B-cell lymphoma.

Dr. Kahl on Findings From the L-MIND Study With Tafasitamab in DLBCL

Ian W. Flinn, MD, PhD, director of Lymphoma Research at Sarah Cannon Research Institute, and the director for the Sarah Cannon Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center, discusses the utility of tafasitamab (MOR208) in patients with relapsed diffuse large B-cell lymphoma (DLBCL).

Tafasitamab would be considered for any patient with DLBCL who has relapsed and is not suitable for other therapies, says Flinn. 

CAR T-cell therapy is a very aggressive treatment option; to receive CAR T cells, patients must be almost as fit as they would need to be to undergo a stem cell transplant. The same almost holds true for patients to receive polatuzumab vedotin (Polivy), which is usually given in combination with bendamustine and rituximab (Rituxan), adds Flinn. In order to be a candidate to receive that combination, patients must have a good hematologic function.

For some patients,that is not a realistic scenario. For example, they could have cytopenias or have previously received multiple chemotherapies, and giving more chemotherapy is not an appropriate approach for them, says Flinn.

As such, tafasitamab, in combination with lenalidomide (Revlimid), is a very appropriate treatment option for that group of patients, concludes Flinn.

Ian W. Flinn, MD, PhD, discusses the utility of tafasitamab (MOR208) in patients with relapsed diffuse large B-cell lymphoma (DLBCL).

Dr. Flinn on the Utility of Tafasitamab in Relapsed/Refractory DLBCL

OncLive® provides updates on the treatment of patients with diffuse large B-cell lymphoma through a Scientific Exchange Workshop. 

Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma | Supplements and Featured Publications