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ASH Data Suggests CAR T is Best Option for Lymphoma Patients Expressing Both MYC, BCL-2


NEW YORK – Researchers exploring the outcomes of patients with so-called "double-expressor lymphoma," or cancers overexpressing both MYC and BCL-2, found these patients do worse on chemotherapy and suggested that they should be prioritized early for CAR T-cell therapies.

In a retrospective analysis presented at the American Society of Hematology's annual meeting on Saturday, researchers analyzed data from seven centers in the UK and explored the prognostic value of double-expressor status in patients with primary central nervous system lymphoma (PCNSL), a subtype of B-cell non-Hodgkin's lymphoma. The analysis included 242 PCNSL patients, most of whom received the MATRix regimen, a chemo and immunotherapy combination treatment that includes methotrexate, cytarabine, thiotepa, and Genentech/Biogen's Rituxan (rituximab).

Edward Poynton, a researcher at the Barts Cancer Institute in London, and colleagues analyzed data from 164 patients with PCNSL, and reported that 40 percent had double-expressor PCNSL by immunohistochemistry. Poynton and colleagues also looked for patients with "double-hit lymphoma" based on the presence of MYC and BCL-2 loci translocations, but there were too few patients with this biomarker to draw any conclusions.

At a median follow-up of 1.7 years, the researchers found that double-expressor status was associated with significantly poorer progression-free survival across all treatment strategies, with a median progression-free survival of a little over 10 months (0.86 years) for double expressors versus 2.77 years for non-double expressors.

When restricted to only patients treated with the MATRix regimen, they found a trend toward inferior progression-free survival and overall survival among double expressors, but it did not reach statistical significance. However, one group of patients with double-expressor status did not appear to have poorer outcomes: those who received MATRix followed by autologous stem cell transplant.

"When we look at cases that received MATRix induction and went on to be consolidated with an autologous stem cell transplant, we can see these cases have the best outcomes in our study," Poynton said. "In this subgroup of 66 cases, we did not demonstrate any significant association of shorter progression-free survival with double-expressor status."

Poynton noted that there isn't currently a standard-of-care based on double-expressor status for primary central nervous system lymphoma and there is more work needed to characterize this subtype of the disease to determine the best treatments.

His group is currently conducting trials that include genomic analysis of patients with double-expressor status to better understand the underlying biology of double-expressor versus non-double expressor primary central nervous system lymphoma.

"For younger, fitter patients who can tolerate intensive chemotherapy, my view is they should receive intensive induction treatments, such as a MATRix-style protocol, followed by autologous stem cell transplantation," he said. "It's going to be a very difficult question to answer because we're already at baseline using highly intensive chemotherapy regimens, and in the future, there's going to be a rationale for more targeted therapies."

Insight into double-hit patients

Another study presented at ASH on Saturday provided some insight into how relapsed or refractory B-cell non-Hodgkin's lymphoma patients who have double-hit status do on CAR T-cell therapy.

Eighty out of 408 lymphoma patients had double-hit lymphoma and received one of three autologous CAR T-cell therapies: Gilead's Yescarta (axicabtagene ciloleucel), Novartis' Kymriah (tisagenlecleucel), and Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel). Researchers also looked at 74 patients with double-expressor status on these therapies.

Researchers led by Joanna Zurko, assistant professor at the University of Wisconsin School of Medicine and Public Health, found that response rate, progression-free survival, and overall survival were similar on these CAR T-cell therapies across both double-hit and non-double-hit lymphoma patients. However, they found double-hit patients who progressed after CAR T-cell therapy had inferior median overall survival compared to non-double-hit patients, 2.7 months versus 6 months, respectively.

Zurko characterized these double-hit patients who relapse on CAR T-cell therapy as high-risk. She said that the data so far "support early use of CAR T in these high-risk patients who traditionally carry very inferior responses to chemoimmunotherapy and autologous stem cell transplantation."

When researchers considered how patients with double-hit and double-expressing lymphomas did on CAR T-cell therapy, response rates were 69 percent and 64 percent, respectively, compared to 66 percent for patients without these biomarkers. Progression-free survival and overall survival were also similar between the three groups. The trial was not designed to explore outcome differences between the specific CAR T-cell therapies patients received or the line of therapy they got.

But the trial does raise questions about what's next for high-risk double-hit lymphoma patients after they progress on CAR T-cell therapy. "These patients were more likely to receive radiation alone and less likely to be enrolled on clinical trials [post-CAR T-cell treatment progression]," Zurko said.

She urged investigators designing trials exploring treatment strategies after CAR T-cell therapy failure to advance more liberal inclusion criteria and give more patients the chance to partake in research. "Given that many double-hit patients were unable to receive treatment on clinical trials, novel strategies to identify CAR T failure should be investigated," she said.