Treatment Considerations in Primary Refractory vs Early-Relapsed DLBCL


In the first article of a 2-part series, Joseph M. Tuscano, MD, discusses at a virtual live event with fellow clinicians how to define early-relapsed or primary refractory diffuse large B-cell lymphoma and how this impacts treatments for this patient population.


A 67-year-old man presented with fatigue, back pain, and lymphadenopathy​ and had hypertension well controlled with medication. A physical exam showed a 1.5-cm left posterior cervical node; a 2.5-cm right anterior cervical node; and 2.0-cm left supraclavicular node. A PET-CT scan multiple enlarged mesenteric and retroperitoneal nodes, with the largest measuring 5.3 x 3.1 cm​. A bone marrow biopsy was negative​ and it confirmed non-GCB diffuse large B-cell lymphoma (DLBCL). His immunohistochemistry test was positive for: CD20, BCL-6, BCL-2 (50% of cells), MYC (greater than 30% of cells), Ki67 (85%), MUM1, but negative for CD10. He had normal CBC​ but his LDH elevated​. He was given a diagnosis of stage III, high-intermediate risk disease with a non-germinal center and ECOG performance score of 1.

R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) was initiated for 6 cycles and his back pain resolved, however, 8 months after completion of therapy he complained of returning symptoms. A palpable lymph node in the left groin was discovered on physical examination​. Scans showed a new left inguinal lymph node, increase in size of residual node, as well as multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis​. Another biopsy confirmed DLBCL, but next-generation sequencing was not performed.

JOSEPH M. TUSCANO, MD: How do you define primary refractory disease versus early relapse? Is there an exact [difference]? We all think that there is, but there is variation in how this is defined, so don’t feel like there’s an absolute right or wrong answer here.

Joseph M. Tuscano, MD


UC Davis Comprehensive Cancer Center​
Sacramento, CA

Joseph M. Tuscano, MD


UC Davis Comprehensive Cancer Center​
Sacramento, CA

MUJAHID RIZVI, MD: Primary refractory [disease] is someone whose disease grows through chemotherapy, or just immediately after stopping treatment has worsening disease.

TUSCANO: I agree with that, so [the disease] grows through treatment or does not have a complete remission.

GIGI CHEN, MD: Yes, this patient would be classified as primary refractory, given the fact that the disease-free interval is only 8 months, so it is less than a year.

TUSCANO: That’s a great point and this definition varies. I think a lot of physicians would say that early relapse would be considered in less than a year. Primary refractory disease might be as well, but there’s variations on this. We could also say that’s how they defined it in the ZUMA-7 [NCT03391466] and TRANSFORM [NCT03575351] trials.1,2

Early relapse was less than a year, primary refractory was if [their disease grew] through treatment, but some [patients on these trials] grew through or did not have a complete remission. Some physicians also define it as within 3 or 6 months of completing therapy, as well.

MING ZHOU, MD: For this patient they did a bone marrow biopsy. How often do you need to do a bone marrow biopsy?

TUSCANO: The only time I do a bone marrow biopsy now is maybe [for patients with] early-stage disease. There are some studies now with PET scans, particularly in patients with Hodgkin lymphoma that you don’t need to do a bone marrow biopsy, even in early-stage disease. But that’s about the only time I do it for patients with DLBCL. But that’s a good point. What does everybody think about the prognosis of a patient like this?

RIZVI: It’s not good.

TUSCANO: Just thinking off the top of your head of the patients that you see, what are the therapeutic options that you would consider for a patient [like this]?

DIANA SUPERFIN, MD: I would refer a patient to a tertiary center for CAR [chimeric antigen receptor] T-cell therapy or transplant.

TUSCANO: To add to that question, would you start salvage therapy and then refer them, or would you wait and hear back?

ZHOU: It depends on the patient’s presentation. If you have to do the treatment early and if their disease progressed fast, then yes, I would do the bridge treatment and refer them.

CHAINARONG LIMVARAPUSS, MD: I would start them on something because it would take some time before they get to you. It’s still going to take a couple of weeks before the patient can see you for a consultation…for CAR T-cell therapy or autologous [stem cell] transplant. They’re going to need something to bridge the gap.

TUSCANO: Yes, that’s very common…. Are there any regimens that you think about in [this case for] these patients?

LIMVARAPUSS: I used to go back to my R-ICE [rituximab, ifosfamide, carboplatin, and etoposide] regimen, which I have not been using very much now since [the introduction of R-GemOx (rituximab plus gemcitabine-oxaliplatin]. My go-to regimen now would be R-GemOx.

TUSCANO: OK, R-GemOx, that’s a reasonable option. Anybody else?

SUPERFIN: The main thing is to cooperate with the center you’re sending the patient. When determining which tertiary center, I’m going [to refer them to], I do discuss with the attending physician what they prefer for this particular situation.

CHEN: [You should] avoid bendamustine [Bendeka] in the patients that you’re planning [to refer to] CAR T-cell therapy.

TUSCANO: That’s absolutely right. That’s now actually specified in the National Comprehensive Cancer Network [NCCN] guidelines, at least before leukapheresis.3 What is your favorite regimen in a setting like this?

CHEN: Maybe something [that includes polatuzumab vedotin (Polivy)].

TUSCANO: That’s a reasonable option. There’s polatuzumab and rituximab, or sometimes lenalidomide [Revlimid] is good, at least until they get their leukapheresis for the CAR T-cell therapy.

SUPERFIN: I think polatuzumab is going to move forward. Polatuzumab has become first line now in the majority of cases, maybe not in this case, but now we’re going to use it as it’s a category 1 recommendation.

TUSCANO: Yes, the POLARIX trial [NCT03274492] showed a [significant] progression-free survival and [polatuzumab is now] FDA approved in the frontline setting.4,5 How does that influence your use of polatuzumab in the relapsed setting? I’ve heard various scenarios, but we don’t really know yet. Would you ever use polatuzumab again in a patient that had polatuzumab plus R-CHP [rituximab, cyclophosphamide, doxorubicin, and prednisone]?

CHEN: Hopefully, [and then] they won’t relapse this quickly.

TUSCANO: A lot have said, and the same thing [goes for] brentuximab vedotin [Adcetris], if the patient fails right away then it probably means that they’re refractory, like [the patient in this case] did. He got polatuzumab plus R-CHP. It probably wasn’t that effective, but if they relapse later then I don’t know…but [it sounds like] most [participants] would try to consult with their tertiary center and others might get somebody started [on therapy] just depending on how acute the patient is.


1. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133

2. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6

3. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 5.2023. Accessed July 25, 2023.

4. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304

5. FDA approves polatuzumab vedotin-piiq for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high-grade B-cell lymphoma. News release. April 20, 2023. Accessed July 25, 2023.

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