L-MIND Study in R/R DLBCL

EP: 1.Standard of Care for Relapsed/Refractory DLBCL

EP: 2.CAR T in Transplant-Eligible and Transplant-Ineligible DLBCL

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EP: 3.L-MIND Study in R/R DLBCL

EP: 4.RE-MIND Study in R/R DLBCL

EP: 5.Phase 2B SADAL Trial in R/R DLBCL

EP: 6.Treatment of R/R DLBCL: Beyond CAR T Therapy

John M. Burke, MD: Let’s transition. In the last year we’ve seen a lot of novel therapies approved in large cell lymphoma, more than anytime that I can remember in my 17, 18 years of practice. To my recollection, we’ve seen approvals of polatuzumab vedotin. In the last month or 2 we’ve seen approvals of selinexor and then the combination tafasitamab-lenalidomide. These are new treatments for all of us and for practitioners around the world. Let’s talk about these treatments. Nathan, I’ll pick on you first to tell us your experience with polatuzumab. That was the therapy approved a year or so ago, along with bendamustine-rituximab. What’s your experience with that? Tell us about the drug and how you use it in your practice.

Nathan H. Fowler, MD: Polatuzumab is a conjugated antibody with MMAE [monomethyl auristatin E] conjugated to an antibody against CD79b. This CD79 is part of the B-cell receptor, so the good news is that target is on all lymphoma cells. The purpose of this study was to combine the novel conjugated antibody with bendamustine-Rituxan [rituximab]. In practice, when we’re treating patients who are either failing chemotherapy or are ineligible for transplant, bendamustine-rituximab is a standard go-to treatment option.

The study that led to the approval of this drug was published by Laurie Sehn and her colleagues, and it’s a pretty simple design. They randomized people, 40 patients in each arm, to either receive BR [bendamustine-rituximab] or bendamustine-rituximab plus pola [polatuzumab vedotin]. It showed me that BR [bendamustine-rituximab], unfortunately, is not a great drug for a lot of these patients. The median overall survival with BR [bendamustine-rituximab] was only about 5 months. When you added polatuzumab, the median overall survival almost tripled to over a year. Complete response [CR] rates were a lot higher, about 17% vs 40%. PFS [progression-free survival]—not surprising with overall survival being longer—was also longer when you added polatuzumab to BR [bendamustine-rituximab]. That was pretty surprising. If you look at the history of these conjugated antibodies like CD22, they have not made that big of an impact in large cell lymphoma. Whether it’s a target or the warhead, it appears that pola [polatuzumab vedotin] had efficacy. What I often wonder is: How would that group have done without BR [bendamustine-rituximab]? Because it looks like BR [bendamustine-rituximab] did not add a whole lot in the refractory population.

The drug is easy to give. It’s an infusion associated with some thrombocytopenia, neutropenia, which was higher in the BR [bendamustine-rituximab]–polatuzumab arm. They also saw some peripheral neuropathy. Overall, the drug is well tolerated. We’re now using it in combination with BR [bendamustine-rituximab] for patients who are transplant ineligible and even in some patients whom we’re trying to get to transplant or who fail other chemotherapies.

John M. Burke, MD: Great. I found that to be useful combination in my practice. For some folks who may have been exposed to BR [bendamustine-rituximab] or have trouble with counts, I can dial down on the bendamustine component, keep the pola [polatuzumab vedotin] dose reasonable, and still get some good results. We know that pola [polatuzumab vedotin], along with rituximab alone, can work well too. That would be my tip for those who are new to that combination therapy

Great. Why don’t you tell us about tafasitamab? I know you have a lot of experience with that drug and some of the trials. You can tell us about the data supporting the recent FDA approval of taf [tafasitamab] and len [lenalidomide].

Grzegorz S. Nowakowski, MD: Tafasitamab was approved in combination with lenalidomide in relapsed/refractory diffuse large B-cell lymphoma [DLBCL]. The FDA deserves credit for recognizing that sometimes for the treatment of this aggressive disease you need doublets. None of the drugs is approved as a single agent. The FDA changed the paradigm and approved the doublet because of high efficacy seen clinically for this combination of patients with relapsed and refractory diffuse large B-cell lymphoma.

If you look at the drug label and that population, tafasitamab-lenalidomide is approved for patients who are not eligible for transplant. Therefore, they are either relapsing after initial induction therapy and are not transplant candidates because of comorbidities—such as performance status, age, or other issues—or they are patients who are not responding to salvage therapy and cannot proceed to transplant or are relapsing after a transplant. It is a broad approval in this regard. Tafasitamab-lenalidomide is also approved for patients with transformed lymphoma, de novo DLBCL, but also patients with relapsed transformed diffuse large B-cell lymphoma are eligible for this combination.

As you mentioned, the approval is based on the L-MIND study, which enrolled patients with relapsed/refractory large cell lymphoma, who have had 1 but no more than 3 lines of therapy and are not eligible for high-dose chemotherapy with autologous stem cell transplantation. Those patients were treated with tafasitamab-lenalidomide. Lenalidomide used here with tafasitamab is actually at the standard dosage, 25 mg daily from day 1 through 21 of a 28-day cycle—the myeloma dosage, if you would, which we are familiar from myeloma studies—but higher than what’s used typically in combination with rituximab, which is 20 mg when used in this setting.

Tafasitamab is initially given weekly for cycles 1 through 3. During the first cycle it’s also given on day 4. Later on, it’s given only on days 1 and 15 as infusion.

In the L-MIND study, the total duration of therapy was 12 cycles. In patients who are responding and having clinical benefit, investigators could continue tafasitamab as a single agent indefinitely because of the limited treatment options otherwise available for those patients. We have a feeling it will be hard to stop giving tafasitamab as a single agent in folks who are potentially benefiting from it.

If you look at the study overall, 81 patients who were treated in the study showed high response rates and longer duration of response. Also, if you look at the characteristics of those patients, as you would expect in this population, many were older. All of them had previous rituximab therapy, of which a high number were either Rituxan [rituximab]–refractory or refractory to most recent therapy.

The primary-refractory patients were excluded from the study; however, the definition of the study changed in its duration. Some of the primary-refractory patients were included in the study, and a subset analysis of those patients didn’t show different results later on than in patients who were not primary refractory.

If we look at the primary end point of the study, the overall response rate was over 60%. It’s a very high response rate. If you look at the CR [complete response] rate, it was about 43%. These are high rates of deep responses. There are 2 important points to note. One is the CR rate or overall response rate because if patients are not responding, they would be lucky to progress. This progression may render patients ineligible for other therapies because of changes in the performance status or other factors. Second, the initial response rate is important because it identifies those patients who benefit. Even if they relapse, they’re positioning into other therapies later on.

Also, the duration of response was quite remarkable. If you look at the initial publication, 72% of the patients had a duration of response of at least 12 months at the cutoff. We’ve recently seen the update in EHA [European Hematology Association Guidelines] with a longer duration of response, now approaching 13 months. Those are durable responses seen with this combination.

What about toxicity? Well, it’s primarily hematological. We see neutropenia. We see thrombocytopenia. Just as you would expect with the combination of IMiD [lenalidomide] and the antibody, the growth factor support was allowed on the study. In practice it will be used to maintain the dosing intensity, which helps with neutropenia and reducing the incidence of neutropenic fever. Thrombocytopenia was seen but wasn’t severe in association with bleeding. The nonhematological toxicity was not common. Infusion reactions were quite rare, which was good to see, because this allowed the infusion to be relatively rapid.

With this combination, we see exciting results with high response rate, durability of response, and the combination can be given to patients with borderline performance status or hematological intensive therapies. You can watch closely for toxicity, adjust the dose of lenalidomide if needed, and use growth factor support if needed to get those patients through therapy.

Transcript Edited for Clarity