Later Lines and Future Directions in DLBCL

EP: 1.Case Review of a 71-Year-Old Woman Presenting With DLBCL

EP: 2.Assessing Risk to Guide First-Line Treatment Selection in DLBCL

EP: 3.Second-Line Therapy Options in DLBCL

EP: 4.The L-MIND Trial in R/R DLBCL

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EP: 5.Later Lines and Future Directions in DLBCL

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.

Transcript edited for clarity.

Case: A 71-Year-Old Woman with R/R DLBCL

Initial presentation

• A 71-year-old woman presented with fatigue, weight loss and pruritus
• PMH: HTN, medically controlled
• PE: palpable axillary and femoral lymphadenopathy; palpable spleen 3 cm below the midclavicular line
• ECOG PS 1
  
  

Clinical Workup

• Labs: Hb 9.8 g/dL, LDH 2x ULN; renal and hepatic function WNL
• Hepatitis B, C and HIV negative
• Excisional biopsy of a right enlarged axillary lymph node confirmed DLBCL, GCB subtype
• IHC positive for: CD10, CD20
• FISH panel: t(14;18) translocation with BCL2 rearrangement, no MYC or BCL2 rearrangements
• Flow cytometry: CD19-postitive
• 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
• Ann Arbor stage IVa DLBCL, GCB subtype
• IPI score high-risk

Treatment

• Treated with R-CHOP x 6 cycles
• 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
• She was offered ASCT but deferred
• Initiated tafasitamab + lenalidomide