Newly Diagnosed DLBCL: Treatment Decision Factors

Brian Hill, MD, PhD: The treatment factors that affect newly diagnosed patients with newly diagnosed diffuse large B-cell lymphoma [DLBCL] include pretty standard clinical features, including age, functional status, and comorbidities. From the perspective of the disease, if the patient has double-hit lymphoma, that can also impact treatment selection.

For the majority of patients who have reasonable performance status, if they’re in their 60s or 70s and don’t have significant comorbidities, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still going to remain the standard in the current era outside clinical trials. If they have significant advanced age in their 80s or late 70s, comorbidities, or really poor performance status starting with less inventive regimens such as mini-R-CHOP [reduced-dose regimen of rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or just palliative treatment with steroids, Rituxan, and cyclophosphamide, or vincristine, like R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] is often used in that setting, that’s appropriate.

Again, for most fit patients who can receive R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], that’s still the standard outside double-hit lymphoma. As we discussed, if a fit patient has double-hit lymphoma, that’s when a more intensive regimen is usually offered.

The stage of diffuse large B-cell lymphoma can impact treatment to a certain extent. Most patients are going to be advanced stage, with stage III or IV, depending on the extent or absence of extranodal disease. Again, for those patients, 6 cycles of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still standard therapy.

In the case of limited stage—so a true stage I—there are data from recent trials that show for low-risk early stage patients, it’s appropriate to offer either 3 or 4 cycles of systemic therapy with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], sometimes followed by radiation. Increasingly we’re seeing data that suggest that if you achieve a complete metabolic response, for instance, after 3 cycles of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], completing systemic therapy with 4 cycles and omitting radiation is still reasonable and achieves very good outcomes for early stage, stage I or II, DLBCL.

For germinal center or nongerminal center, which is said to be activated B-cell subtype, there have been a number of trials over the past decade that have attempted to improve the outcome of patients with higher-risk, nongerminal center, DLBCL, which usually has an activated B-cell phenotype. Investigators have attempted to introduce proteasome inhibitor bortezomib, lenalidomide, BTK [Bruton tyrosine kinase] inhibitors such as ibrutinib. To make a long story short, all these trials have not been positive.

Despite the significant biological rationale for introducing targeted agents for these subtypes of patients, particularly the ABC [activated B-cell] subtype, none of the studies has panned out. Some of this may be related to patient selection in terms of not getting the higher-risk patients on the studies. Another part of this is likely that the method of assigning subtypes has been too crude, and we really need to move to a more advanced molecular testing method to discriminate the subtypes and then assign targeted agent pathway inhibitors, targeted agents in those specific pathways for those specific subtype.

Andre Goy, MD: This is an important aspect. When you see patients having comorbidities and cardiac issues, neurological issues, etc, we know that this is a difficult situation. The definition is the geriatric assessment, but basically if it’s an older patient, more than 80 years old and with some comorbidities, you can use an attenuated form of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], which is the mini-CHOP [reduced-dose regimen of cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. That could be very helpful. If the patients have cardiac dysfunction, we can replace the doxorubicin with etoposide or gemcitabine, or liposomal doxorubicin. Sometimes bendamustine–Rituxan [rituximab] will be used, sometimes combinations with antibody-drug conjugates that are being looked at in the frontline setting. Hopefully other combinations will emerge as a possibility.

In patients who are older, it’s important to mention here—the patients that are older, frailer, a bit but not necessarily cardiac dysfunction—1 thing that works really well is to give them somewhat of a prephase with vincristine, rituximab, and steroids for 5 days. Then they come back a week later and then we can get them started on R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. These patients do really well.

There’s finally novel therapy, as I mentioned, that might offer an opportunity to replace chemotherapy in that setting. There are the R2 [lenalidomide, rituximab]–ibrutinib data from The University of Texas MD Anderson Cancer Center, from the SMART START trial from Jason Westin. That has shown very high response rates and CR [complete response] rates after an induction that is basically nonchemotherapy option: response rate of 80% and CR over 36%. These patients can receive an abbreviated course potentially of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] if they’re elderly. As I alluded to the polatuzumab, POLA, is used in the relapsed/refractory setting. We’ll talk a little later about this, but it is going to be integrated as well as bevacizumab is integrated in a frontline setting. We are building up by adding these types of therapy that might allow us to treat, even better, these patients who have comorbidities and issues that prevent them from using anthracycline.

Transcript Edited for Clarity