P53-Mutated MCL Remains Difficult to Treat

Tycel Jovelle Phillips, MD

Mutations in the p53 gene are associated with poor prognosis for patients with mantle cell lymphoma (MCL). Although modern regimens have improved outcomes, those treatments are associated with significant toxicity and, so far, have produced limited efficacy, said Tycel Jovelle Phillips, MD.¹

Phillips, a clinical associate professor with the University of Michigan Rogel Cancer Center, assessed current treatment and potential future options for p53-mutated MCL during a presentation at the 2022 Pan Pacific Lymphoma Conference.

“MCL, as most of us know is a very rare but difficult to treat lymphoma subtype,” he said. “For the most part, it is very heterogeneous in how we approach it and how we see it. There are a multitude of different opinions on the best way to treat every patient and all of us think we’re right. But, in the end, none of us probably are.”

Phillips started with the questions: does autologous transplantation help overcome prognostic risk associated with p53 alterations and does any chemotherapy really overcome these p53 alterations?

“If we look at the historical data, it appears that [for] p53 mutations, which [are] probably the most adverse of the 2 alterations that we can see with p53, there’s really no benefit to chemotherapy. There’s really no benefit to autologous stem cell transplantation, which is really still all chemotherapy,” he said. “So, in this patient population, what can we do to move the needle versus the other 70% to 80% of the patients with MCL [for whom it] probably doesn’t matter what we give them up front versus these more high risk patients?”

Phillips explained that the presence of a p53 mutation is not necessarily an indication to initiate treatment. Investigators have detected the mutation in patients with slow-growing MCL.

“Although it does appear to affect long-term outcome compared with other indolent, non-nodal patients, they typically still have better outcomes [compared with] classical, more aggressive patients,” Phillips said. “Nothing that we’ve seen so far in the literature suggests that treating these patients right away really will move the needle or push the curve.”

Data from most prospective studies show that agents such as ibrutinib (Imbruvica), and lenalidomide (Revlimid) do not appear to have a role to play in the treatment of these patients, Phillips said. He added that venetoclax (Venclaxta) may be effective as part of a combination, but the current evidence does not support its use as monotherapy.

In June 2022, Michael L. Wang, MD, of The University of Texas MD Anderson Cancer Center, and colleagues published data from phase 3 SHINE trial (NCT01776840) evaluating ibrutinib plus bendamustine and rituximab (Rituxan) vs bendamustine/rituximab alone in patients aged 65 years or older with untreated MCL. Patients were randomly assigned to 560 mg of once-daily ibrutinib (n = 261) or placebo (n = 265) plus 6 cycles of 90 mg/m² of bendamustine and 375 mg/m² of rituximab.²

Patients with an objective response received rituximab maintenance therapy every 8 weeks for up to 12 additional doses. The primary end point was investigator-assessed progression-free survival (PFS).

At a median follow-up of 84.7 months, the median PFS was 80.6 months in the ibrutinib group vs 52.9 months in the placebo group (HR, 0.75; 95% CI, 0.59-0.96; P = .01). Patients in the ibrutinib arm were more likely to have a complete response (65.5% vs 57.6%; P = .06) but overall survival was similar in the two groups.

Among patients with p53 mutations, the addition of ibrutinib did not demonstrate a clear PFS benefit (HR, 0.95; 95% CI, 0.50-1.80).

The incidence of grade 3/4 adverse effects was 81.5% in the ibrutinib group and 77.3% in the placebo group.

“From this indication from the SHINE study, this combination is not something that necessarily will move the curve ahead in these patients who have p53 mutations,” Phillips said.

Investigators are hoping to have more success with findings from a trial (NCT03824483) evaluating the combination of zanubrutinib (Brukinsa), obinutuzumab (Gazyva), and venetoclax known as BOVen. In phase 2 data published in December 2021, BOVen produced high rates of undetectable minimal residual disease (MRD) as initial therapy for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).³

The primary end point of the study is the established rate of undetectable MRD at 1 year. During the study, all patients received zanubrutinib at a dose of 160 mg and obinutuzumab at 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 through 8. During cycle 1, obinutuzumab was administered as a split dose at 100 mg on day 1 and 900 mg on day 2. Venetoclax was added starting cycle 3.

Forty-seven patients enrolled from March 2019 to October 2019. Thirty-nine went on to receive protocol therapy and 37 were analyzed for activity. All 39 were analyzed for safety.

The median age of patients was 62 years (interquartile range, 52-70), 77% were male, and 90% were non-Hispanic white. The median lymphocyte count per uL was 43400. Thirteen percent of patients had 17p deletion or a p53 mutation.

At 2 months, undetectable MRD was present in 3% of patients. Twenty-eight percent had undetectable MRD at 4 months, increasing to 56% at 6 months. At 8 months, 81% had undetectable MRD. Ninety-five percent of patients had undetectable MRD in the peripheral blood, and 89% had undetectable MRD in the bone marrow.

At 2 months, the overall response rate (ORR) was 92%. At 6 months, the ORR was 97%, with a complete response (CR) rate of 25%. At the time of treatment discontinuation, the ORR was 100%, with a 55% CR rate.

Five patients with p53-mutated MCL are currently enrolled and investigators are still recruiting patients for this cohort. Phillips said “the jury is still out” regarding efficacy for the BOVen combination for this population. “More long-term follow up is needed to get a readout on how effective and durable this treatment is in this patient population.”

Phillips concluded by saying that patients with these mutations should be treated differently than others with MCL. Furthermore, it appears they do not derive benefit from chemotherapy.

“In my practice, for any patient who has a p53 mutation, I’m not going to waste time with toxicity from chemotherapy knowing that the remissions will be very short,” he said. “The patients, when we have them, I will counsel, ‘I will put you on a BTK inhibitor because it’s the best thing I can give you at this point. You will likely relapse within 24 months, at which point we refer you to CAR T unless we have a clinical trial.’”

References

1. Phillips TJ. Should we be treating p53 mutated mcl differently? Presented at: 2022 Pan Pacific Lymphoma Conference: July 18-22, 2022; Koloa, HI.
2. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. 2022;386(26):2482-2494. doi:10.1056/NEJMoa2201817
3. Soumerai JD, Mato AR, Dogan A, et al. Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2021;8(12):e879-e890. doi:10.1016/S2352-3026(21)00307-0