CD19-Directed Antibody-Drug Conjugates for DLBCL

Part 1: Selecting Third-Line Options for DLBCL With CAR T-Cell Therapy

During a live virtual event, Ann LaCasce, MD, MMSc, discusses third-line treatment options for diffuse large B-cell lymphoma when considering eligibility for chimeric antigen receptor T-cell therapy.

CASE SUMMARY

A 79-year-old man presented with fever, 7-lb unintentional weight loss, and occasional chest pain​. He had a history of medically-controlled hypertension. A physical exam showed palpable bilateral cervical lymphadenopathy​.

Laboratory results showed a lactate dehydrogenase level of 300 U/L (280 U/L upper limit); hemoglobin of 10.8 g/dL; bilirubin level of 1.3 mg/dL (1.2 mg/dL upper limit); creatinine 1.7 mg/dL (1.2 mg/dL upper limit); and all others within normal limit​s. The patient was negative for Hepatitis B, C, and HIV.​

A lymph node biopsy was performed. The immunohistochemistry panel revealed CD10+, CD20+ diffuse large B-cell lymphoma (DLBCL), germinal center B-cell like subtype. Fluorescence in situ hybridization was negative for rearrangements of BCL6, BCL2, and C-MYC​.

A whole-body PET/CT scan showed activity in the colonic wall, with a largest node of 3.9 cm and evidence of subcutaneous tissue involvement​. An MRI of the brain showed no evidence of lesions​. The cancer was classed as stage IV with an International Prognostic Index of high-intermediate risk, and an ECOG performance score of 1.

The patient received 6 cycles of rituximab (Rituxin), cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate (Oncovin), and prednisone (R-CHOP), which was well-tolerated​. A PET/CT scan at the end of treatment showed complete remission​.

One year later, the patient presented with diffuse lymphadenopathy, confirmed by a PET CT scan​. A biopsy showed relapse of the same DLBCL​. The patient was considered ineligible for transplant​.

He completed second-line rituximab, gemcitabine, and oxaliplatin [R-GemOx] with partial response​, but 5 months later, he presented with overt disease progression​.

DISCUSSION QUESTION

  • What are the key factors that influence your decision making for third-line therapy, such as eligibility for allogeneic transplant, chimeric antigen receptor (CAR) T-cell therapy, patient preference, and the tolerability of the regimen?​

ANN S. LACASCE, MD, MMSC: So, what do people think at this point? What would be your choice of the number of options that we have now for a patient like this, who’s elderly but relatively well. Sounds like his performance status is quite good, but he had a relatively brief duration of remission to R-GemOx.

JOSEPH ANTIN, MD: I would not take him for allogeneic transplant, because if he’s not eligible for an autologous transplant, he’s certainly not eligible for an allogeneic transplant.

LACASCE: What about CAR T-cell therapy? Is this something that you would think about and refer your patients for?

ANTIN: Personally, I think that at 79 years old, he’s a little on the old side for that. I don’t know that we have a specific age cutoff, but, my experience with 79-year-olds is that that they [can be more likely to have neurological issues], and when you add neurotoxicity on to that, I think it’s a questionable approach for someone that age, particularly with his underlying renal and hepatic dysfunction.

LACASCE: Absolutely. I think the renal dysfunction is a big issue with the conditioning, which includes fludarabine. And these patients often have relatively poor stem cell reserve, and when you give them the lymphodepletion, and then the CAR T-cell therapy, they often end up with prolonged cytopenias. We have lisocabtagene maraleucel [Breyanzi], but we don’t have as much experience with that because it’s more recently approved, and the data suggests that perhaps it’s more tolerable, but I think we have yet to really see that for sure.1

MARK SHPARBER, MD: I would probably use polatuzumab vedotin [Polivy]. I use it as second-line treatment in [a similar patient], got about 14 or 16 months out of it, and used it again. He did not want to go for any opinions up north, did not want to even talk about autologous or allogeneic transplant. So, I used it twice, on 2 different occasions. Unfortunately, it’s very short-lived.

LACASCE: Do you give it with bendamustine [Bendeka]?

SHPARBER: Yes, I gave it with [bendamustine and rituximab].

LACASCE: We’ve had some trouble getting the bendamustine in. It is a very active drug.

SHPARBER: I think that is due to the [recommended 1.8 mg/kg] dose. I only gave him 60 mg to 70 mg.

LACASCE: Yes, but it’s otherwise a very well-tolerated drug. I think the convenience logistics is always a big issue for patients of this age, and we see a lot of referrals from up north and down south, and that is definitely something we think about.

What proportion of your patients with relapsed/refractory DLBCL receive CAR T-Cell therapy?

CASE SUMMARY

  • CAR T-cell therapy was discussed as an option, but the patient declined due to long distance to the nearest transplant center​.

This patient declined due to distance to the nearest transplant center. We certainly see that, and as we talk to patients about potential toxicity and the need to be within 2 hours of the transplant or CAR T-cell center, as well as not being able to drive for 2 months, that [rules out] a subset of patients.

What would you most likely recommend for this patient in the third-line setting after chemoimmunotherapy?

LACASCE: So, for this patient, what would you recommend? Loncastuximab tesirine [Zylonta]; polatuzumab vedotin plus or minus bendamustine and rituximab; Selinexor [Xpovio]; tafasitamab [Monjuvi]/lenalidomide [Revlimid]; or, something else? So 75% chose polatuzuamb/bendamustine/rituximab, and then 25% chose loncastuximab.

Have you used polatuzumab/bendamustine? It’s a well-tolerated drug; the neuropathy doesn’t seem as predominant, I would say, as we see with maybe brentuximab, but obviously it’s not being given with a neurotoxic drug. Have you seen fevers after giving polatuzumab?

SHPARBER: Yes. I premedicated with Tylenol.

LACASCE: It is more myelosuppressive than even bendamustine/rituximab alone.

Reference:

1. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0