New Strategy for Unmet Need in Relapsed/Refractory DLBCL - Episode 1

Approaching Newly Diagnosed DLBCL

Matthew J. Matasar, MD:For a patient with newly diagnosed large-cell lymphoma, I would say that there isn’t a single standard approach. We really try to approach each individual patient taking into account their distribution of disease, their burden of disease, and the goals of care for that individual patient.

The first question we would ask is, how confident are you with the diagnosis? We know that second-opinion pathology review is critically important both in diffuse large B-cell lymphoma as well as across the spectrum of lymphomas. Making sure that the diagnosis has been confirmed by an expert hematopathologist is extremely valuable.

Once we’ve confirmed a general diagnosis of diffuse large B-cell lymphoma, we then might want to look additionally at the individual biology of that patient’s disease. Individual therapeutic approaches may differ based on cell of origin or other biological features. Here we would think about sort of de novo diffuse large B-cell lymphoma versus a double-hit, or high-grade large-cell lymphoma.

The cell of origin, whether it’s germinal center or nongerminal center, may influence certain decisions, such as whether or not to administer treatment to prevent recurrence in the central nervous system [CNS].

That being said, the first question in terms of the overall therapeutic approach is, what stage is the patient? We divide diffuse large B-cell lymphoma into sort of stage I or stage II, or early-stage large-cell lymphoma, or advanced stage.

Early stage is important because we know that some subset of patients who have early-stage disease can be treated with less overall therapy. And here, the decisions that we make in the treatment of early-stage large cell lymphoma include whether or not to give combined modality therapy—3 cycles of anthracycline-based chemotherapy, such as R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone], followed by radiation therapy. Or can you just give a chemotherapy-only approach?

We have data using 4 cycles of R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone] chemotherapy with 2 additional doses of rituximab afterward from the important FLYER trial, and this showed noninferiority for 4 cycles of therapy as compared with 6, making this a very reasonable standard of care for appropriately selected early-stage large-cell lymphoma patients.

For advanced stage disease, R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone] chemoimmunotherapy remains the standard of care. There have been a number of attempts over the years to try to improve upon R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone] chemotherapy, either with the substitution of agents or addition of other agents. None of these trials have ever borne fruit, in terms of establishing a therapeutic approach that is superior to—meaning improved overall survival for the overall treated patient population—R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone] alone.

The recent PHOENIX trial was a negative trial. This was a randomized trial of R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone] versus R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone] plus ibrutinib in nongerminal center patients. A subset analysis suggested that it’s possible that in younger patients, maybe there could have been an overall survival benefit had it been restricted to such a subset of patients. However, that was not how the study was conducted. And we, in the field, view this as a negative trial and do not routinely recommend R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone] plus ibrutinib, even in younger patients with nongerminal center large-cell lymphoma.

For patients with high-grade lymphoma, many experts in the field continue to recommend a modified program known as rituximab and dose-adjusted EPOCH [etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride], or R-EPOCH [rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride]. This admittedly remains an area of some controversy, and the data are not convincing. Nonetheless, many experts do recommend the use of R-EPOCH [rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride] for high-grade lymphomas, or double-hit lymphomas.

The decision regarding whether to administer prophylactic high-dose methotrexate continues to be an area of evolution. Historically, many experts recommended intrathecal methotrexate injections for patients who have been felt to be at-risk for CNS [central nervous system] relapse. This is consistently and increasingly being understood as an ineffective approach. For those patients who we believe do require CNS prophylaxis, we would usually recommend incorporation of high-dose methotrexate, either during the course of chemotherapy or following achieving a complete remission with R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone]—based treatment.

The majority of patients who are treated with rituximab and CHOP [cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisolone]—based chemotherapy in the first line will be cured—the majority, but certainly not all patients. The likelihood of cure is influenced by disease biology and individual characteristics—you know, crude prognostic systems such as the IPI [International Prognostic Index] or the Revised IPI. There certainly is a subset of patients with high-risk disease who face real risks of failing to achieve a complete response—or even if achieving a complete response, subsequently suffering relapse.

Transcript edited for clarity.