A Deep Dive Into Double-Hit Lymphoma

Double-hit lymphoma — a rare and aggressive subtype of diffuse large B-cell lymphoma (DLBCL) — was first categorized as a specific diagnosis 10 years ago.

However, it is “an evolving term,” explained Jason Westin, MD, of the University of Texas MD Anderson Cancer Center in Houston.

A gene rearrangement is referred to as “a hit,” Westin told MedPage Today, adding that in the case of double-hit lymphoma, those rearrangements had included the MYC gene alongside BCL2 and/or BCL6. Then, in 2024, the fifth edition of the WHO classification of hematolymphoid tumors made major changes to the definition.

The category now consists of MYC and BCL2 rearrangements exclusively, while the MYC/BCL6 double-hit lymphomas now constitute genetic subtypes of DLBCL not otherwise specified (NOS), or of high-grade B-cell lymphoma NOS.

According to the authors of a review of the WHO classification, the reason for the change is that “aggressive lymphomas with a MYC/BCL2 double hit form a homogeneous group with respect to [gene expression profiling] and the mutational profile, whereas MYC/BCL6 [double-hit] lymphomas are heterogeneous in nature.”

In any event, double-hit lymphoma traditionally has a poor prognosis, with inferior rates of progression-free survival (PFS) and overall survival compared with non-double-hit lymphoma when treated with a conventional regimen like rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP).

It also makes for a challenging diagnosis.

“The only way that we know if a disease is double hit versus regular diffuse large B cell is from the pathology team,” Westin said. “We may have a suspicion because the patient is very symptomatic or has a significant disease burden, or has a very high LDH [lactate dehydrogenase], which is a blood test that’s sometimes a prognostic marker. But short of the pathology test, any of those could be large B-cell lymphoma or double-hit lymphoma.”

“What patients and community doctors should know is that this really has to be tested by the pathologist,” he added.

However, if a pathologist has not performed fluorescence in situ hybridization (FISH) analysis for a newly diagnosed patient, then patients and doctors “are kind of flying blind,” Westin noted. “Under the microscope, these diseases can look the same on a PET scan and the clinic exam room.”

Thus, a FISH analysis is “a bedrock, fundamental test that needs to be part of the initial workup for doctors to be fully informed about what is the best treatment option for that patient,” he pointed out.

As for treatment, if the disease is localized and if the International Prognostic Index is low, double-hit lymphoma is usually going to be treated like regular large B-cell lymphoma. However, that rarely happens, Westin acknowledged.

“Most patients with double-hit lymphoma have advanced-stage and high-risk disease, and so most double hits are treated differently than large B-cell lymphoma,” he explained, and usually require intensive chemoimmunotherapy.

The regimen most commonly used is dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH), with retrospective and prospective studies showing good outcomes.

For instance, a single-arm, phase II study testing the regimen in patients with double-hit or triple-hit lymphoma showed a 4-year event-free survival rate of 73%, which was significantly higher versus historical controls.

Unfortunately, “about half of our  patients with double-hit lymphoma are going to eventually need treatment after initial therapy for relapsed or refractory disease,” Westin said. “In that situation, you really have to choose the optimal therapy because you may not get a second or a third or a fourth chance at getting the right treatment for a disease that can be quite aggressive, and patients can get sick quickly if they don’t get effective treatment in the relapsed setting.”

“If you give a treatment like R-EPOCH in the first-line setting and that doesn’t work, that’s pretty intense chemotherapy,” he added. “And if the cancer shrugs that off and doesn’t get much of a response, it’s very unlikely that a second attempt at chemotherapy is going to work much better. So, chemotherapy is not the preferred option for people with relapsed double-hit lymphoma.”

The better option is to try to start chimeric antigen receptor (CAR) T-cell therapy as quickly as possible in the hope that it can overcome the poor prognosis associated with standard therapy, Westin said, with a multicenter analysis showing that there was no difference in PFS between patients with double-hit and non-double-hit lymphoma when treated with CD19-directed CAR T-cell therapy.

Phase III Trials

From an investigational standpoint, “the reality is that the disease is relatively uncommon and it’s difficult to do a randomized trial comparing treatment A versus treatment B specifically in this disease setting,” said Westin.

He pointed out that while most clinical trials investigating frontline treatments for large B-cell lymphoma include patients with double-hit lymphoma, the numbers are usually small.

“So, the advances we’re seeing in phase III trials for large B-cell lymphoma are really underpowered in their evaluation for patients with double-hit lymphomas,” he noted.

That said, Westin and colleagues are conducting a phase III trial — ZUMA-23 — evaluating the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) versus standard of care (either R-CHOP or dose-adjusted R-EPOCH) as first-line therapy in patients with high-risk large B-cell lymphoma, defined as an International Prognostic Index of 4/5 — a score that many patients with double-hit lymphoma present with.

“So, I think it will have an enrichment for double-hit lymphoma much greater than we’ve seen from the POLARIX trial or the frontMIND trial,” Westin said.

The POLARIX trial established polatuzumab vedotin (Polivy) in combination with R-CHOP minus vincristine as a new standard of care for patients with previously untreated intermediate-risk or high-risk DLBCL, while frontMIND showed that combining tafasitamab (Monjuvi) and lenalidomide (Revlimid) with R-CHOP improved PFS compared with R-CHOP alone as a first-line treatment for newly diagnosed high-risk DLBCL and high-grade B-cell lymphoma.

However, less than 10% of patients in the POLARIX and frontMIND trials had double-hit lymphoma — too few for a meaningful subgroup analysis.

“I think it’s reasonable that the population of [double-hit lymphoma patients] in the axi-cel trial is going to be significantly greater,” Westin said, adding that the study may support moving CAR T-cell therapy into the first-line setting for these patients.

In the second-line setting, the PiNACLE-H2H trial will compare rondecabtagene autoleucel, a dual-targeting CD19/CD20 CAR T-cell therapy, with investigators’ choice of CD19 CAR T-cell therapy in patients with aggressive relapsed or refractory large B-cell lymphoma.