Part 1: Decision-Making for Third-Line Treatment of Transplant-Ineligible DLBCL

Beth A. Christian, MD (Moderator)

Associate Professor, Division of Hematology

Director, Hematology and Medical Oncology Fellowship Program

The James Cancer Hospital - The Ohio State University Comprehensive Cancer Center

Columbus, OH

CASE SUMMARY

A 75-year-old man presented with fever, 7-lb unintentional weight loss, and occasional chest pain. He had a history of hypertension, which was medically controlled. A physical examination indicated a tired appearance and a palpable bilateral cervical lymphadenopathy. Laboratory investigations were as follows: lactate dehydrogenase, 300 U/L (280 U/L upper limit); hemoglobin, 10.8 g/dL; bilirubin, 1.3 mg/dL (1.2 mg/dL upper limit); creatinine, 1.7 mg/dL (1.2 mg/dL upper limit); all others were within normal limits. He was hepatitis B, hepatitis C, and HIV negative. Immunohistochemical testing of lymph node biopsy specimens identified CD10+, CD20+ diffuse large B-cell lymphoma [DLBCL] of the germinal center B-cell–like subtype. Fluorescence in situ testing indicated that the tumor was negative for rearrangements of BCL6, BCL2, and C-MYC. A whole-body PET/CT scan showed activity in colonic wall; the largest node was 3.9 cm, and there was evidence of subcutaneous tissue involvement. MRI of the brain showed no evidence of lesions. The man was diagnosed with stage IV disease; his International Prognostic Index was high-intermediate risk, and his ECOG performance stats was 1.

The patient received 6 cycles of rituximab (Rituxan) plus cyclophosphamide plus doxorubicin hydrochloride plus vincristine [R-CHOP], which was well-tolerated. A PET/CT scan at end of treatment showed complete remission. One year later, patient presented with diffuse lymphadenopathy, which was confirmed by PET/CT scan; a biopsy showed relapse of the same DLBCL. The patient was considered ineligible for transplant. He completed second-line rituximab plus gemcitabine plus oxaliplatin [R-GemOx], with partial response, but 5 months later he presented with overt disease progression.

DISCUSSION QUESTION

• What are some of the key factors that influence your decision-making for third-line therapy?

BETH A. CHRISTIAN, MD: What are some of the key factors that influence your decision-making for third-line therapy [in a patient like this]?

ANEEL CHOWDHARY, MD: I think that we’re not sure if using anti-CD19 therapy early on will have any impact on [therapeutic response to subsequent] CAR [chimeric antigen receptor] T-cell therapy.

I refer patients to get CAR T-cell therapy early on. Once the patient has had relapsed or refractory DLBCL after first-line therapy, I start the referral process right away. I think [early use of] CAR T-cell therapy should be considered, and maybe the other anti-CD19 therapies could be used afterward.

CHRISTIAN: I agree. I think that the decision about third-line therapy is often made after [the patient fails] first-line therapy. [This decision depends on] the what the patient‘s treatment goals are. For young, fit patients, my approach has been to give second-line therapy, and if they achieve a complete response, to proceed to autologous stem cell transplant [ASCT]. I think the more challenging situation, now with the options that we have, is for patients who are not fit for ASCT but who may be fit more CAR T-cell therapy. [In these patients, the challenge is to consider] how to optimally sequence their lines of therapy. I think early consideration of CAR T-cell therapy is important. I definitely try to avoid [using] bendamustine [Treanda] prior to T-cell collection if I’m contemplating CAR T-cell therapy for the patient.

Do see a fair number of patients that you feel are ineligible for ASCT but you would consider for CAR T-cell therapy? What do those patients look like in your practice?

YACOUB FAROUN, MD: We don’t do CAR T-cell therapy in our institution; we send patients for a second opinion to see whether they are candidates. While I think the patient needs to be capable of staying in the outpatient setting for at least 10 days and having good family support, I do not know [what other factors make them] fit for CAR T-cell therapy. I know that use of polatuzumab vedotin [Polivy] might affect the collection of T cells for CAR T-cell therapy. So, I think that giving anti-CD19 therapy prior to CAR T [is appropriate].

MARK KNAPP, MD: The National Comprehensive Cancer Network [NCCN] guidelines caution against using bendamustine and CD19 antibodies prior to CAR T-cell therapy.¹ What should we use as second-line treatment for patients in whom we are truly thinking of CAR T-cell [therapy for third-line treatment]? Would you recommend second-line treatment with something like R-GemOx?

CHRISTIAN: Yes, I think that in patients that you are certain are not fit for ASCT, using a more intensive second-line therapy such as R-ICE [rituximab, ifosfamide, carboplatin, etoposide], R-DHAP [rituxiumab, dexamethasone, ara-C, cisplatin], or R-GDP [rituximab, gemcitabine, dexamethasone, platinum] may be too aggressive.

R-GemOx is something that I have used in that situation. I don’t think that the impact of anti-CD19 therapy before CAR T-cell therapy [is really known], although there are some limited data emerging on this. Options include using lenalidomide [Revlimid] alone or [in combination with other agents]. Although it’s off label, using polatuzumabvedotin alone without the bendamustine is a potential consideration.

NEERAJ MAHAJAN, MD: I think that CAR T-cell therapy is the biggest elephant in the room right now. Things keep evolving and rapidly changing, and we are already hearing about [promising results from] second-line therapy trials comparing [CAR T-cell therapy] with stem cell transplant.

I would like to see all patients [with relapsed or refractory disease after first-line therapy] to get evaluated for CAR T-cell therapy as soon as possible. The last thing you want to do is give something like bendamustine that could impair the patient’s chances for that. [Right now], CAR T-cell therapy is a third-line treatment option, but fairly soon we may have another patient subset who are not eligible for transplant, but are eligible for [second-line] CAR T-cell therapy. I think in 6 months or a year from now, CAR T-cell therapy might be the default second-line treatment option. I’m not sure, but it looks like we are moving that way.

CHRISTIAN: Definitely. It sounds like we should really give all patients the potential option for CAR T-cell therapy, and then move on if they’re not candidates or if they’re unwilling.

_Reference:

_{1. NCCN. Clinical Practice Guidelines in Oncology. B-Cell Lymphomas, version 5.2021. Accessed November 22, 2021. https://bit.ly/30Rq9dl}