Treatment Options in Transplant-Ineligible DLBC Lymphoma

This content originally appeared on our sister site, Targeted Oncology.

Grzegorz S. Nowakowski, MD and Stephen D. Smith led a Case Based Roundtable event in which participants discussed treatment for patients with transplant-ineligible diffuse large B-cell lymphoma (DLBCL).

SMITH: By the time patients get to our center, they usually have committed the effort, the logistics, and the perception [regarding their being] a transplant candidate. But I think those issues may be more in the community. I’d really like to hear how other physicians think that aren’t located at a transplant center. But for us, [patients are ineligible for transplant because of] insufficient response to salvage [therapy], failure to collect [cells], or a lot of times accumulated toxicities during salvage treatment or during R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone]. They get 4 or 5 cycles of R-CHOP and they progress and/or get a significant infection. You wonder how appropriate it is to consider transplant.

I think the toxicities from prior lines of chemotherapy also have a major influence. But I’d be curious about the perceptions of others with regard to desire to transpant. Is there an age cutoff that you all would consider as transplant-ineligible? Is it logistics or perception of treatment-related mortality? What would you say about maybe the top 2 reasons in your practice?

DY: I’m a community oncologist. I do my best to partner with the tertiary center and ours is also the University of Washington. I would refer the majority of my patients and let the transplant center make that decision. But I would say probably the easiest way to deem somebody ineligible for transplant would be the multiple comorbidities and the performance status. I wouldn’t necessarily have an age cutoff because there are a lot of good performance statuses in the elderly population. Then I let the transplant center decide most of the time.

GOLDBERG: I agree. I think we’re close enough to Seattle, so there’s no problem with the tertiary care and access issues. But comorbidities and performance status are usually the deciding point. A lot of them are obvious, but if someone’s on the borderline, we’ll still refer them up there for an opinion on whether it’s possible.

SMITH: We now have an explosion of drug approvals for patients who are transplant ineligible or at least after 2 prior lines. That and the advent of effective CAR [chimeric antigen receptor] T-cell therapies that changed the discussion around our historical KarMMa data [NCT03361748] around transplant. Patient preference has something to do with it, but we regard transplant as curative and we would like to give most patients a shot, if that’s a reasonable summary of what I’m hearing.

NOWAKOWSKI: Those are the patients who never achieve remission or relapse very close to the end of therapy.

SMITH: I think the number of truly refractory patients who really progressed during R-CHOP therapy is relatively low. I think the numbers—and this may be different than individual experiences—are probably 10% to 15% that are truly primary refractory. If you lump that in with the people that relapse within the first 3, 6, or 9 months, you start to build a picture of early relapse plus refractory. Then you have your positive PET scan at the end of treatment that you’re calling a partial response, but you don’t feel great about it and you don’t know necessarily which way that’s going to go.

I would like to also dig in and see if that percentage sounds like about what people experience in their practice. If they’re treating 5 or 6 patients in a year, is it 1 patient who might be truly refractory or is it 2 or 3 depending on the biologic features maybe?

KOSIEROWSKI: I would agree with those numbers. [It’s] very rare to see someone primarily refractory. The biggest problem is the early relapse.

NOWAKOWSKI: That has been our experience as well. The truly progressing patients are exceedingly rare. Patients who do not achieve complete metabolic response might be a bit more common. But again, it’s not a very frequent phenomenon and early relapse seems to be the biggest problem for a lot of these patients.

NOWAKOWSKI: When you’re thinking about your choices, what influences your selection of therapy? Is it the chance for long-term response, safety, tolerability, comorbidities, patient preference, or any other factors which you take into account to decide between various available options for those patients? We already mentioned some.

DY: I think for me the biggest thing would be if the patient is transplant eligible or not, which then would encompass all of these questions of can the patient tolerate it, can they tolerate more chemotherapy, how aggressive the chemotherapy would be. What are the comorbidities? What are the adverse events from the previous chemotherapy?

If we think that a patient can still be eligible for transplant, then I would be aggressive with my chemotherapy and I would still try those other regimens like RICE [rituximab, ifosfamide, carboplatin, etoposide] and R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin]. Then depending on the good response or not, proceed with transplant. If I think the patient is ineligible, then that’s when I would probably use either R-GemOx or [one of the many] other CD19 and CD30 targets, plus CAR in the later line.

ARORA: I would also throw in the availability of clinical trial if there is something available. That would be preferable in this situation, if [the patient is] eligible.

NOWAKOWSKI: How do you usually identify a trial? Do you have it at your institution or do you try to refer for the trials or a mix of both?

ARORA: Both. There are some trials that we have and then Fred Hutchinson Cancer Research Center is around the corner for us. Referral and distance is not an issue.

SMITH: I think Dr Dy’s point is critical. That first decision on if a patient is transplant eligible means you’re going down the road of proving chemotherapy sensitivity and trying to get as high of a complete remission [CR] rate as you can but using a regimen that has a standard intensive platinum backbone and then perhaps adding a drug in some of the trials. We’ll add a novel agent to those intensive platinum regimens, and you have to see how that goes in that subgroup of patients. It’s the patients who either progress or right at the outset you know aren’t going down that path that it opens wide up to all of the other drugs. But I completely agree that that’s how we also look at that first decision tree.

GOLDBERG: What about the decision in the beginning once you get the patient in CR and you don’t know yet what’s going to happen about storing their marrow [after first-line therapy]?

SMITH: Our preference at our institution is to try not to wait it out to 3, 4, or 5 cycles of any platinum therapy. We try to get [bone marrow tests] after 2, maybe 3, cycles. But also, with plerixafor and modern methods, we’re able to [get] stem cells out of the marrow at a fairly high rate, so chemotherapy mobilization and plerixafor have reduced the urgency in making that decision too early, I think.

NOWAKOWSKI: That’s a great point. Our practice is similar. We used to collect some of those patients’ [cells] who are particularly high risk. We did a small retrospective study here that [showed] we rarely use those cells and we can usually collect them now with plerixafor. That seems to be not commonly used nowadays.

GOLDBERG: Did you not use them because people didn’t relapse?

NOWAKOWSKI: Some folks did relapse, but then they have chemorefractory disease, some other reason, or something happened. They couldn’t get to stem cell transplant anyway. Then some people just did not relapse, so it was a mix. But overall we found that we’re using only about 15% to 20% of stored stem cells later on. Most of them were just not used and remained in storage for quite some time and then we abandoned this practice for that reason.

NOWAKOWSKI: It looks like there was a spread [across] the answers. About 11% of folks thought about CAR T-cell therapy, a third thought about low-intensity chemotherapy, high-intensity chemotherapy was 11%, and the combination of tafasitamab [Monjuvi] and lenalidomide [Revlimid] was 44%. Nobody voted for other options because most of them would either fall under low-intensity or high-intensity chemotherapy, presumptively, outside of the clinical trial.

SHENOI: Would polatuzumab [Polivy] plus bendamustine and rituximab [Rituxan; pola-BR] be a good comparable regimen for this group in the relapsed setting?

SMITH: It would be. The study [NCT02257567] included patients with 1 prior regimen, but pola-BR wasn’t able to achieve a fairly high CR rate.1 However, the progression-free survival [PFS] of that regimen was inferior and when you look at their expanded sets of patients they included in later analysis, it was always well under a year of PFS. You also get infectious toxicity with pola-BR in my experience and in subsequent real-world publication that’s been significant. But you’re right, we need to keep our perspective here. There are other options. There will be some patients more suitable for a slightly more intensive regimen where CR rates can be achieved with pola-BR as well, it’s just that the durability and the chemotherapy toxicity have to be considered.

NOWAKOWSKI: The comparisons of the studies are always difficult because you’re capturing different patient populations. That’s why we need to randomize studies to answer some of those questions or we can try to closely match those patients as much as we can nowadays in the real-world data studies.

But Dr Smith’s point is a good one because you don’t necessarily see the same tail in a pola-BR combination, which we see with [tafasitamab/lenalidomide] in terms of PFS and duration of response.2 We’ll see what additional follow-up will show up on the studies, but so far, those results are quite unprecedented in terms of the duration of response and the PFS curves outside of the CAR T-cell therapy and more aggressive solo approaches.

SMITH: For me, the logistics in the real world are always a little challenging. Certainly, trials have their own challenges in getting patients synchronized, for example. But with tafasitamab and lenalidomide, you’d like to start them on time. You want to give growth factor support. You need to consider the dose reductions carefully. It’s not an extremely simple regimen to give, although I get the point that we’ve given lenalidomide fairly frequently across hematologic malignancies, so familiarity is high. But I think the logistics of the regimen are a little complex, just as one example. Any other limitations [regarding why you] might not…use this routinely?

KOSIEROWSKI: Cost is always a factor.

SMITH: Cost for prescription drug coverage in lenalidomide remains a factor. Insurance remains highly unpredictable and a quick time [suck] for your week for many patients with prior authorization and appeals.

NOWAKOWSKI: Would you consider CAR T-cell therapy after tafasitamab if there is a disease progression? I personally would, particularly if the CD19 expression was there, but I’m curious [about] your opinion.

SHENOI: This group of patients is non–transplant eligible, so it’s unlikely that they’d be eligible for CAR T after that.

SMITH: That’s a really interesting point. I agree that there is some overlap in eligibility there, but I think increasingly, many investigators are considering CAR T-cell therapy, given the somewhat less-intensive lymphodepletion chemotherapy and the attenuated neurotoxicity in cytokine release syndrome that we’re seeing with new CAR T-cell therapies, [which are] significantly less toxic than autologous transplant.

Now, that may be in the eye of the beholder and we need good comparative studies, but I think there are CAR T candidates who are not transplant candidates out there. But I completely agree with the point in general; in principle, there is a lot of overlap between those groups. This question I think is more getting at the CD19 aspect and whether we’d consider sequencing CAR T after exposure to that drug. The answer for me is yes.

REFERENCES

1. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172

2. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4