Matthew Lunning, DO

: If a patient were to progress on tafasitamab and lenalidomide, part of the options then go into polatuzumab, bendamustine, and rituximab, which I talked about as a regimen. I don’t believe it’s approved in the second-line setting in relapsed/refractory diffuse large B-cell lymphoma, but it is after 2 prior lines of therapy. That would be an option for this patient. Another option would be a discussion around CAR [chimeric antigen receptor] T-cell therapy. Even though in this setting the patient chose not to proceed to intensive second-line therapy and the potential for an autologous transplant, it would be worth having a discussion around whether CAR T would be of interest to her. We would have to note the caveat that there’s very little if any experience of prior tafasitamab exposure, which perturbs the CD19 antigen on the lymphoma cells, in those people who are relapsing or progressing after that then to go off and get a CD19-directed therapy after exposure.

I don’t think we’re going to see clinical trials that are going to necessarily have this situation of tafasitamab, lenalidomide followed by CAR T, but I hope that we’ll get some experience in clinical trials where the trials aren’t excluding prior CD19 exposure in the third line, so that we may see if there can be efficacy for CAR T in this setting. There are other chemotherapy regimens like R-GemOx [rituximab, gemcitabine, oxaliplatin]. There’s selinexor, which is approved in this setting. I have shied away, now that the Pola-BR [polatuzumab, bendamustine, rituximab] data are out, using just bendamustine alone in this setting given the randomized phase 2 data of Pola-BR [polatuzumab, bendamustine, rituximab].

There’s been a lot of progress very quickly in relapsed/refractory diffuse large B-cell lymphoma. Other emerging therapies are obviously the bispecific therapies, these bispecific T-cell engagers that directCD3 T cells to either a CD19 or a CD20 arm that brings them together and activates the T cell. These do have similar [adverse] effects that CAR T cells do in the third line or beyond setting from that standpoint.

Another unmet need is understanding more around what’s going to happen in the second-line setting in regard to CAR T-cell therapy in those patients who are transplant eligible. There are 3 randomized trials looking at high-risk patient populations and whether CAR T is superior to second-line therapy and autologous stem cell rescue, which is still standard of care in those individuals who proceed. In this clinical case scenario with this patient relapsing likely within a year of therapy, I would classify her as a patient with high-risk large cell lymphoma.

The next question in future directions, we’re challenging not only in the frontline setting with drugs like polatuzumab in combination with chemotherapy but also looking at the activity of tafasitamab, lenalidomide and seeing if that activity together can be combined with a chemotherapy backbone to improve the outcomes of frontline diffuse large B-cell lymphoma. Because the best chance of curing large B-cell lymphoma likely resides in the frontline setting. Trying to improve upon first-line outcomes is a major initiative in research.

The next question of where does CAR T cell fit, I know the ZUMA-12 trial looked at those patients who had positive PETs [positron emission tomography scans], who had CAR T, I believe after 2 lines of therapy, and had high-risk features for their diffuse large B-cell lymphoma. Those outcomes look interesting, but we have to wait for that data to mature in the frontline setting.

Practical advice I could offer community oncologists treating diffuse large B-cell lymphoma is, if there’s concern about early progression during chemotherapy, interim scans would be reasonable. If you’re concerned about relapse or you find relapse early after frontline therapy, referral to a center that provides autologous stem cell transplant and potentially cellular therapy would be an option to help have the discussion about transplant eligibility. Not everybody’s going to choose transplant. It may not be what they feel is in their best interest, but they have to potentially understand the intent of second-line therapy with deferring autologous stem cell transplant. And if they do defer therapy, then there are options that aren’t transplant in the second line, but it’s a very delicate discussion to have and one that can be done in concert with a transplant center. Often those transplant centers are also CAR T-cell centers. I believe…CAR T can be a discussion also for if second-line therapy doesn’t work, or moving it potentially into the second line if the trials are positive in the future.

A 71-year-old woman presented with fatigue, weight loss and pruritus

PE: palpable axillary and femoral lymphadenopathy; palpable spleen 3 cm below the midclavicular line

Labs: Hb 9.8 g/dL, LDH 2x ULN; renal and hepatic function WNL

Excisional biopsy of a right enlarged axillary lymph node confirmed DLBCL, GCB subtype

FISH panel: t(14;18) translocation with BCL2 rearrangement, no MYC or BCL2 rearrangements

Whole body PET/CT scan showed FDG avidity in the bilateral axillary and femoral regions, largest lymph node 3.6 cm in right axillary space; splenomegaly

Bone marrow biopsy showed involvement of DLBCL in the bone marrow

First post-treatment PET/CT scan unremarkable; metabolic CR based on Deauville criteria

9 months later there was relapse of disease with new cervical and mediastinal lymphadenopathy

Core needle biopsy of a cervical lymph node confirms a relapse of DLBCL, GCB subtype

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Dr Lunning reviews potential options for later line therapy for patients with R/R DLBCL and shares his thought about future directions in the evolving treatment landscape. 

Later Lines and Future Directions in DLBCL

: In this case the patient did elect to go on to tafasitamab, lenalidomide. Looking at the L-MIND data, tafasitamab is a CD19 monoclonal antibody that has been studied as a monotherapy, but has also been studied and found to be synergistic with lenalidomide, at least in vitro models. This was tested in the L-MIND setting for patients with relapsed/refractory diffuse large B-cell lymphoma. What I found interesting about the L-MIND data is that individually, lenalidomide in relapsed/refractory large B-cell lymphoma and tafasitamab did not appear to have individually high overall response [OR] rates or high CR [complete response] rates. But when you add them together, those overall response rates and CR rates went up significantly above what each individual drug would’ve brought to the table. The other thing was you were seeing response rates that had the ability to be durable. That’s been the most impressive part of the tafasitamab, lenalidomide data, that you can get patients with relapsed/refractory diffuse large B-cell lymphoma into a remission, and then those remissions could be durable. Often in relapsed/refractory diffuse large B-cell lymphoma, patients do achieve an early response, but that response has difficulty being durable, and that’s often reflected in the progression-free survival curves.

What does this mean for the patient? Well, the way that the lenalidomide, tafasitamab regimen is structured, with tafasitamab given I believe 13 doses in the first 3 months, as well as lenalidomide dosed at 25 mg on a 21-out-of-28-day basis, can give a lot of therapy that you need to get the disease under control early on. With this dosing strategy, I believe it does afford patients to have the opportunity for remission, and then the lenalidomide and tafasitamab is continued. The lenalidomide’s continued for up to a year, and the tafasitamab is continued indefinitely every other month after the third cycle.

With that, one of the other parts of the L-MIND data that intrigued me was the ability to maintain dose intensity. I believe over 8 out of 10 of the patients on the study were able to continue on 20 mg or greater of lenalidomide. I’ve found it can be difficult to get 25 mg or even 20 mg of lenalidomide into patients with relapsed/refractory diffuse large B-cell lymphoma. Perhaps this is because I’ve often, prior to this regimen, used it in later lines of therapy, where the patients have seen much more chemotherapy then if you were giving it in, for instance, the second-line therapy.

Also thinking about the long-term outcomes from the L-MIND study, what’s been impressive is that the duration of remission appears to continue to hold, at least in the clinical trials. As it gets out into the commercial environment, it’ll be interesting to see in the post-marketing phase whether that long-term duration of remission can be achieved outside of a clinical trial. The toxicity profile…I think is interesting because lenalidomide toxicities in my mind are potentially rash early on, tumor flares, but also [blood cell] count suppressions. And so being able to manage neutropenia, anemia, thrombocytopenia with dose reductions as well as with growth factor support. There can be the risk of infusional reaction with tafasitamab, and obviously infections with both drugs in combination. But it appears that those infusional reactions can be managed with supported medications.

Then people start talking about maintenance therapies. What’s interesting in this regimen is the lenalidomide was continued for 12 cycles and then dropped, and the tafasitamab continued. Whether you call this continuation of therapy or maintenance therapy just because you drop one of the drugs, and likely those people are obtaining a clinical benefit whether they’re a CR or a PR [partial response]. I think you must realize that if you’re using this in a relapsed/refractory large cell lymphoma setting, it’s very unique for a patient to still be in a remission at 12 months…especially when you’re not giving intensive chemotherapy and consolidating with an autologous stem cell transplant. In my mind, if the patient’s tolerating tafasitamab at the end of the 12th cycle, I would likely continue maintenance therapy every 2 weeks. We don't have a lot of data to my knowledge of lengthening the tafasitamab dosing regimen to let’s say every 4 weeks or every 6 weeks. And so short of that data, in this situation where a patient is doing well from a response standpoint, unless there are toxicity issues, I’d likely discuss with them continuing it every 2 weeks.

Matthew Lunning, DO, presents the efficacy and safety findings of the L-MIND trial in relapsed/refractory diffuse large B-cell lymphoma and discusses the implications for clinical practice.

The L-MIND Trial in R/R DLBCL

: In this setting regimens like R-ICE, [rituximab, ifosfamide, carboplatin, etoposide], R-DHAP, [rituximab, dexamethasone, cytarabine, cisplatin], or R-GDP [rituximab, gemcitabine, dexamethasone, cisplatin]—which are likely equivalent second-line regimens that may induce a response amenable to be consolidated with an autologous stem cell transplant—would be reasonable discussions to have. In this setting you’re talking about a potential curative intent.

However, some patients may not want to elect to go onto intensive chemotherapy and an auto transplant, understanding that without doing this, this may not lead to further therapies being performed with curative intent. In that setting, if they do have all the information and know that potentially they’re deferring a curative intent second-line therapy…. Given that this is coming back within 9 months from the end of her frontline therapy, this is one of those types of diffuse large B-cell lymphomas that I would argue is poor risk and runs a high risk of not obtaining a response amenable to transplant. But you don't know that unless you actually get that second-line regimen from that standpoint.

If a patient wasn’t going to go toward an autologous stem cell transplant-consolidated regimen, I’m not sure that I would choose second-line regimens like ICE [ifosfamide, carboplatin, etoposide] or DHAP [dexamethasone, cytarabine, cisplatin]without the intent to go on to consolidated transplant. If the patient decides that the transplant is not for them, then I’m not sure that I would use those regimens without that intent. Then in this case, given the tafasitamab, lenalidomide data in the second- and third-line settings, this would be a reasonable option given that she had what one could consider a very short remission duration to chemotherapy, likely denoting an underlying biology that would be “chemotherapy refractory” or less likely to respond to a second-line standard chemotherapy-based regimen, or for instance a gemcitabine-based regimen like gemcitabine, oxaliplatin.

Another option in the second line, in a nontransplant setting, would be bendamustine, polatuzumab, rituximab. And in this case again, looking at the data regarding the duration of remission, while this might be an option, I also get concerned about the chemotherapy refractoriness potentially of this disease.

Dr Matthew Lunning reviews second-line treatment options for patients with R/R DLBCL and provides insight on individualizing therapy.

Second-Line Therapy Options in DLBCL

: When describing the risk factors for this individual’s lymphoma, one would be her advanced age, marching down the IPI [International Prognostic Index] score, greater than 60. Also, the staging of her disease. She had advanced stage disease with involvement of the bone marrow and likely involvement of the spleen, given that it was enlarged despite there being no avid bone lesions. I would consider doing bone marrow aspirates even if there’s no avid bone lesions in a patient who has anemia at the time of diagnosis. She also had an elevated LDH [lactate dehydrogenase]as well as extranodal sites of disease in the bone marrow biopsy and potentially spleen. In that regard, her performance status was acceptable at the time of diagnosis, so that would make her IPI score a 4 at this point.

Another part about the risk of her assessment of her diffuse large B-cell lymphoma is where she was treated. She was well at this time. Many times, patients treated as inpatients because the diffuse large B-cell lymphoma is making them sick or compressing the airways, may portend a worse overall outcome, as well as the time needed between diagnosis and treatment. Those patients who are started sooner may have overall, at least the literature has shown, they have a little better prognosis than if it takes weeks before you initiate therapy. I have used prognostic factors of the IPI as well as the FISH [fluorescent in situ hybridization]characteristics. If this individual had a double-hit lymphoma, meaning…a high-grade B-cell lymphoma harboring 

 rearrangements, I would consider that a potentially high-risk biologic feature. And in this case, if the patient is felt to be able to tolerate anthracycline-based therapy, I would discuss using dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab] in this setting, noting that I would dose adjust based upon hematologic and systemic tolerance.

There are certain caveats regarding frontline therapy given that R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] vs dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab] are my 2 standard regimens. If I do have time to wait for the molecular testing to come back, I would consider waiting to see whether I’m going to start R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab]. Often if the patient is mildly symptomatic, I may use a prephase-like therapy with prednisone for 100 mg for 5 days. I haven’t classically introduced vincristine into that, which I know was the original prephase. Also, there can be some insight into whether there’s potentially a double hit based upon if your pathologists are able to do 

 expression, high Ki-67, then it may portend that this could be a 

-altered diffused large B-cell lymphoma from that standpoint.

Typical response rates that you could expect from R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], when you’re dealing with diffuse large B-cell lymphoma, the intent is curative. In many situations we’re using full dose R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or full dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab], at least at the initial line of therapy. I focus more on the complete response [CR] rates, now that we’re talking about using responses in the Deauville scoring era and the PET positron emission tomography]/CT era. I would venture that you see metabolic CR rates in between the 60% to 80% range, depending upon the studies that you’re doing. The majority of the people following R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] chemotherapy for frontline diffuse large B-cell lymphoma will often have evidence of remission.

In this situation, the patient did have evidence of recurrent disease defined as diffuse large B-cell lymphoma. It’s important to point out that this was found on physical examination with cervical lymphadenopathy, and further radiographic evidence confirmed this, that the patient also went under a second biopsy. This can be important because sometimes people can have what we call retrograde transformations. If you note here on the initial presentation, there was evidence of a translocation 14;18 as well as 

 expression, which may denote that there could be a follicular lymphoma that this may have derived from. Or if it’s relapsing, there could be follicular lymphoma that’s relapsing and not necessarily diffused large B-cell lymphoma. In this case, we had the comment that the patient tolerated R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] well, and she had a good performance status and no major toxicities during her R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. You could have the discussion, and in this setting, I would have the discussion, about second-line therapy, and autologous stem cell transplant as a curative-intent option.

DLBCL expert Matthew Lunning, DO, describes risk assessment in patients with DLBCL and how it informs first-line treatment choice.

Matthew Lunning, DO | Authors

Articles

Later Lines and Future Directions in DLBCL

The L-MIND Trial in R/R DLBCL

Second-Line Therapy Options in DLBCL

Assessing Risk to Guide First-Line Treatment Selection in DLBCL