A Deep Dive Into Double-Hit Lymphoma

Double-hit lymphoma– an uncommon and aggressive subtype of scattered big B-cell lymphoma (DLBCL)– was very first classified as a particular medical diagnosis 10 years ago

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

A gene rearrangement is described as “a hit,” Westin informed MedPage Todayincluding that when it comes to double-hit lymphoma, those rearrangements had actually consisted of the MYC gene along with BCL2 and/or BCL6. In 2024, the 5th edition of the WHO category of hematolymphoid growths made significant modifications to the meaning.

The classification now includes MYC and BCL2 rearrangements solely, while the MYC/BCL6 double-hit lymphomas now make up hereditary subtypes of DLBCL not otherwise defined(NOS), or of top-quality B-cell lymphoma NOS.

According to the authors of an evaluation of the WHO category, the factor for the modification is that “aggressive lymphomas with a MYC/BCL2 double hit form a homogeneous group with respect to and the mutational profile, whereas MYC/BCL6 lymphomas are heterogeneous in nature.”

In any occasion, double-hit lymphoma generally has a bad diagnosis, with inferior rates of progression-free survival (PFS) and general survival compared to non-double-hit lymphoma when treated with a standard routine like rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP).

It likewise produces a difficult medical 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 stated. “We may have a suspicion because the patient is very symptomatic or has a significant disease burden, or has a very high LDH , 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 included.

If a pathologist has actually not carried out fluorescence in situ hybridization (FISH) analysis for a recently detected client, then clients and physicians “are kind of flying blind,” Westin kept in mind. “Under the microscope, these diseases can look the same on a PET scan and the clinic exam room.”

Hence, 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 explained.

When it comes to treatment, if the illness is localized and if the International Prognostic Index is low, double-hit lymphoma is typically going to be dealt with like routine big B-cell lymphoma. That hardly ever occurs, 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 described, and generally need extensive chemoimmunotherapy.

The program most frequently utilized is dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH), with retrospective and potential research studies revealing great results.

A single-arm, stage II research study evaluating the routine in clients with double-hit or triple-hit lymphoma revealed a 4-year event-free survival rate of 73%, which was considerably greater versus historic controls.

“about half of our  patients with double-hit lymphoma are going to eventually need treatment after initial therapy for relapsed or refractory disease,” Westin stated. “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 included. “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 much better choice is to attempt to begin chimeric antigen receptor (CAR) T-cell treatment as rapidly as possible in the hope that it can get rid of the bad diagnosis related to basic treatment, Westin stated, with a multicenter analysis revealing that there was no distinction in PFS in between clients with double-hit and non-double-hit lymphoma when treated with CD19-directed CAR T-cell treatment.

Stage III Trials

From an investigational perspective, “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,” stated Westin.

He mentioned that while the majority of scientific trials examining frontline treatments for big B-cell lymphoma consist of clients with double-hit lymphoma, the numbers are generally little.

“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 kept in mind.

That stated, Westin and associates are performing a stage III trial– ZUMA-23 — examining the CAR T-cell treatment axicabtagene ciloleucel (axi-cel; Yescarta) versus requirement of care (either R-CHOP or dose-adjusted R-EPOCH) as first-line treatment in clients with high-risk big B-cell lymphoma, specified as an International Prognostic Index of 4/5– a rating that lots of clients 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 stated.

The POLARIX trial recognized polatuzumab vedotin (Polivy) in mix with R-CHOP minus vincristine as a brand-new requirement of take care of clients with formerly neglected intermediate-risk or high-risk DLBCL, while frontMIND revealed that integrating tafasitamab (Monjuvi) and lenalidomide (Revlimid) with R-CHOP enhanced PFS compared to R-CHOP alone as a first-line treatment for recently detected high-risk DLBCL and state-of-the-art B-cell lymphoma.

Less than 10% of clients in the POLARIX and frontMIND trials had double-hit lymphoma– too couple of for a significant subgroup analysis.

“I think it’s reasonable that the population of in the axi-cel trial is going to be significantly greater,” Westin stated, including that the research study might support moving CAR T-cell treatment into the first-line setting for these clients.

In the second-line setting, the PiNACLE-H2H trial will compare rondecabtagene autoleucel, a dual-targeting CD19/CD20 CAR T-cell treatment, with private investigators’ option of CD19 CAR T-cell treatment in clients with aggressive fell back or refractory big B-cell lymphoma.