CD19 As a Therapeutic Target In Diffuse Large B-Cell Lymphoma - Episode 2
Loretta Nastoupil, MD, and John Burke, MD, provide an overview of different prognostic factors that have been identified in diffuse large B-cell lymphoma (DLBCL).
Loretta Nastoupil, MD: What other predictive or prognostic factors do you consider [in patients with diffuse large B-cell lymphoma (DLBCL)]?
John Burke, MD: I still use the good, old-fashioned international prognostic index [IPI], which incorporates the 5 factors that probably most oncologists know: age, performance, status, LDH [lactate dehydrogenase] extranodal sites, and stage. The other key [factors] are the results of a FISH [fluorescence in situ hybridization] panel looking for gene rearrangements of MYC, BCL-2, and BCL-6. Of course, we know that having a MYC rearrangement and then rearrangements in BCL-2 and/or BCL-6 confer a less favorable prognosis. These so-called “double-hit” or “triple-hit” lymphomas are officially called “high-grade B-cell lymphoma with rearrangements of MYC and BCL-2 and/or BCL-6.” In the WHO [World Health Organization] classification, that is separated out and considered a different entity from regular DLBCL, not otherwise specified, even though they look relatively the same under the microscope.
I struggle a little bit [in knowing] how to treat those patients. We know that conventional R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate (Oncovin), prednisone] does not work terribly well, that the outcome is less favorable, and that nonrandomized studies have demonstrated improved outcomes with [use of] more aggressive regimens. With the randomized trials showing that a dose-adjusted EPOCH [etoposide, prednisone, Oncovin (vincristine sulfate), cyclophosphamide, hydroxydaunorubicin] regimen did not confer any benefit when compared with the R-CHOP regimen in patients with regular DLBCL, I question whether that is the more aggressive regimen. Dose-adjusted EPOCH-R [EPOCH plus rituximab] used in a randomized trial would lead to a better outcome in these [patients with] double-hit [disease]. I confess that I use something like dose-adjusted EPOCH for most patients, but I question whether it's truly better. There is certainly doubt in my mind. What is your approach at [The University of Texas MD Anderson Cancer Center] for some of those, and what prognostic factors do you [examine]?
Loretta Nastoupil, MD: I think the challenge that we sometimes face is [that] we'd love to give the high IPI [integrated pulmonary index] protocol, particularly to those high-risk patients, such as patients with double-hit lymphoma [who are] double-expressors [those who overexpress MYC and BCL2 proteins unrelated to chromosomal rearrangements]. Often, they come in sick, and we're pressed to start them on treatment sooner rather than later. And any of the trials that require a substantial amount of screening tests or tissue at baseline then pushes those patients towards a more standard approach.
We have been using dose-adjusted EPOCH-R for our [patients with] double-hit [disease]. Outside of [patients with] double-hit [lymphoma], we might use it for [patients diagnosed with] Burkitt-like or high-grade lymphomas who don't have the traditional rearrangement that qualifies them as a having a double-hit lymphoma. However, for the reasons you mentioned, I also struggle with whether that is the preferred approach or just the approach we're very skilled at initiating quickly, because these patients often will even be hospitalized. Some data have created some controversy recently, given the retrospective look using the Flatiron dataset. It suggests that it's hard to identify a subgroup of patients that truly may benefit from dose-adjusted EPOCH-R. Until we have something better, I'd say that's probably the most common debate we have internally.
John Burke, MD: I think of [The University of Texas MD Anderson Cancer Center] as [being] a hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), and dexamethasone] institution. I know that regimen has been tested in [patients with] double-hit [lymphoma]. Is that something you have moved away from?
Loretta Nastoupil, MD: Yes, we have. It was mostly based on a single-center, randomized phase 2 [study] that Yasuhiro Oki [lead medical director at Genentech, Inc, in South San Francisco, California] did a number of years ago, looking at hyper-CVAD versus R-CHOP in patients with an IPI of 2 or higher. In that setting, we tended to see higher CR [complete response] rates with hyper-CVAD. However, at the end of the day, overall survival was no different, and there were more toxic events for patients who [received] hyper-CVAD. As a result, we stopped using hyper-CVAD, at least in [patients with] large cell lymphoma. We were quick to adopt the dose-adjusted EPOCH-R regimen in the absence of having a randomized study to inform that selection. It’s a little bit easier in terms of tolerability, and you don't alternate, which makes it easier for patients. [Generally,] I prefer EPOCH over hyper-CVAD, but it's not because we've had great studies.
John Burke, MD: For sure, it's easier to administer.
Transcript edited for clarity.