Considerations for Third-Line Therapy for Relapsed/Refractory DLBCL

Brad Haverkos, MD, MPH, MS

Associate Professor, Medicine-Hematology

University of Colorado School of Medicine

Aurora, CO

CASE SUMMARY:

A 73-year-old woman presented with fever, headaches, and 7-lb unintentional weight loss​. She is married with 2 grown children who live in other states; she is the primary caretaker for her mother who has advanced dementia, with no family history of cancer. She has hyperlipidemia, well controlled with simvastatin. Physical examination shows palpable bilateral cervical lymphadenopathy​. Laboratory results include lactate dehydrogenase of 300 U/L (280 U/L upper limit); hemoglobin of 10.8 g/dL; bilirubin 1.3 mg/dL (1.2 mg/dL upper limit); and creatinine 1.7 mg/dL (1.2 mg/dL upper limit); with all others within normal limits. She is negative for hepatitis B, C, and HIV. A lymph node biopsy with immunohistochemistry panel shows she has CD10+, CD20+ confirmed diffuse large B-cell lymphoma (DLBCL); fluorescence in situ hybridization is negative for rearrangements of BCL6, BCL2 and C-MYC​.

A whole-body PET/CT scan showed diffuse adenopathy, largest node 3.9 cm, and MRI of the brain showed no evidence of lesions. Her ECOG performance status is 1. Her DLBCL is ​stage III, International Prognostic Index low-intermediate risk​. ​

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The patient received 6 cycles of R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone, which was well-tolerated​ and led to a complete remission (CR) at the end of treatment. One year later, the patient presents with diffuse lymphadenopathy, confirmed by PET CT scan​. A biopsy shows relapse of the same DLBCL​. She received 6 cycles of pola-BR​ [polatuzumab vedotin (Polivy), bendamustine (Bendeka), and rituximab, and had stable disease for 6 to 8 months before progression​. She is not able to travel because she is the primary caretaker for her mother who has dementia​. She receives loncastuximab tesirine (Zynlonta) as third-line therapy. ​

DISCUSSION QUESTIONS

• Do you agree with the treatment choice for this patient? ​
• What other therapeutic options could be considered? ​

BRAD HAVERKOS, MD: I am curious what you all think about management of this patient so far…mainly focusing on the relapsed setting choices. [She received] R-CHOP, then pola-BR, then loncastuximab.

IOANA HINSHAW, MD: This patient is still [relatively] young at 73 years old and she doesn’t have any other comorbidities. I understand she has a poor social situation being the only caregiver, but on the other hand, it seems to me like we’re not doing a curative approach anymore. I wonder why she wasn’t considered for an autologous bone marrow transplant because that’s still the only curative approach as far as we know. All the other treatments are adequate, but they will basically just prolong her survival.

HAVERKOS: Yes, and certainly, we have good data. Even if we were to decide that this patient is transplant ineligible, there are good data [showing that] older patients who are transplant ineligible can receive lisocabtagene maraleucel [liso-cel; Breyanzi] safely based on the PILOT study [NCT03483103], so it is certainly something to consider.¹ But, if she opts not to go to CAR [chimeric antigen receptor] T-cell therapy and taking care of her mother is more important—you know how it goes sometimes. Patients make their own choices. I don’t know if you have come across this similar situation, but… in a post-CAR T-cell setting or in patients who don’t want CAR T-cell therapy, other than pola-BR, [do] you have any experience with other drugs?

HINSHAW: I have used tafasitamab [Monjuvi] in combination with the lenalidomide [Revlimid]. That’s all I’ve used.

SANTHOSH AMBIKA, MD: If a bispecific is an option, I would probably go with the bispecific in the long term. The long-term data [showed] that patients who achieve a CR with glofitamab-gxbm [Columvi] remain in CR forever and looks like some of them are getting cured.²

HAVERKOS: Yes, maybe.

AMBIKA: I think we shouldn’t say it’s no longer a curative setting; if they respond completely, they may be cured.

BENJAMIN SCHEIER, MD: Are there a lot of [data for] using 2 ADCs [antibody-drug conjugates] in a row and they’re both targeted? They’re different targets but I’m curious if that loncastuximab data included people treated with polatuzumab or not.

HAVERKOS: I don’t remember how many patients received polatuzumab in the LOTIS-2 study [NCT03589469]. But we do have some [data] on loncastuximab. There was a population treated on that trial, some of whom had relapsed after CAR T-cell therapy.³ There was a heavily pretreated patient population, but I don’t remember off the top of my head how many were previously treated with polatuzumab per se.

SCHEIER: But they could have had polatuzumab.

HAVERKOS: Yes. But it’s a good question, whether the ADC [still has efficacy].

SCHEIER: [It is like giving] more chemotherapy, just a different target, right?

HAVERKOS: Certainly, [that’s a] good point. Any other comments?

AMBIKA: I had a patient who had CAR T-cell therapy. It was kind of an experimental protocol, but then he relapsed. In the second biopsy, there was loss of CD19, so then there’s no point in trying loncastuximab in that case, right?

HAVERKOS: There are some data using loncastuximab in CD19-negative patients.⁴ It gets into maybe how you’re measuring CD19, as IHC, flow [cytometry], or other even more sensitive [means]. How much CD19 do you have to have on the cell for it to work?

But it is targeting CD19, so presumably you have to have some CD19 on the cell but it might be below the sensitivity of the assay. That may be enough.… In the LOTIS-2 trial there were about 10% of patients who had been previously treated with a CAR T-cell therapy who did get loncastuximab.³ Obviously, the CAR T-cell therapy and loncastuximab are targeting CD19 and some of those patients did respond. But there’s more than 1 mechanism of resistance to CAR T-cell therapy, it’s not just loss of CD19. It’s hard to know but I think it is an option. This patient didn’t get CAR T-cell therapy, so I think targeting CD19 is certainly an option and something to consider.

SHIVEN B. PATEL, MD, MBA: Have you ever used both loncastuximab and tafasitamab/lenalidomide sequentially? They’re both going after CD19.

HAVERKOS: I don’t think that I have off the top of my head. I know that it has been done by some of my colleagues. To be honest, we don’t use a whole lot of tafasitamab/lenalidomide [at the University of Colorado Anschutz Medical Campus]. I think that’s just because we have CAR T-cell therapy. As opposed to the majority of [the participants at this event], for whom 25% of the patients are getting CAR T-cell therapy, I would say that 75% of our patients get CAR T-cell therapy. It’s a different population that we end up seeing, and so I just use a bit less tafasitamab/lenalidomide. I don’t like targeting CD19 prior to CAR T-cell therapy. Tasitamab is a CD19 monoclonal antibody and so I prefer not to target that antigen and then give them a CD19 CAR T-cell therapy. That’s just been my practice.

[Still], loncastuximab is a drug worth considering. I’ve used it a number of times. To Dr Ambika’s point earlier about some of the BiTEs [bispecific T-cell engagers], having what seemed like durable responses, if you look at some of the patients who got loncastuximab who got into CR, they have pretty lengthy remissions as well, so I think you could probably argue the same thing about some of those patients that respond.

_REFERENCES

_{1. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23(8):1066-1077. doi:10.1016/S1470-2045(22)00339-4}

_{2. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913}

_{3. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X}

_{4. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018;131(10):1094-1105. doi:10.1182/blood-2017-10-813493}