TP53 Mutations Identify Patients With “Highly Aggressive” Mantle Cell Lymphoma

Patients with TP53-mutated mantle cell lymphoma (MCL) have poor overall survival (OS), compared with patients without the mutation. In an analysis of two trials evaluating standard treatment regimens consisting of modern cytarabine-containing induction therapy followed by autologous hematopoietic cell transplantation (AHCT), the presence of these mutations identifies patients who do not benefit from aggressive chemoimmunotherapy, noted Christian W. Eskelund, MD, from the Department of Hematology at Rigshospitalet in Copenhagen, Denmark, and co-authors.1

“The intensified standard-of-care regimens for younger [patients with] MCL do not overcome the deleterious effects of TP53 mutations,” the researchers wrote in their report published in Blood. Given the poor results seen in this patient population, they “should be considered for alternative frontline treatment.”

The authors analyzed bone marrow samples from the 183 patients (median age = 56 years; range = 29-65 years) enrolled in the Nordic MCL2 and Nordic MCL3 trials who were evaluable for genetic analyses. The MCL2 and MCL3 trials included a total of 319 patients with MCL who were treated with an induction phase of alternating R-maxi-CHOP (rituximab [R], cyclophosphamide, daunorubicin, vincristine, prednisone) and R-high-dose cytarabine, followed by high-dose chemotherapy with BEAM (carmustine, etoposide, cytarabine, melphalan) or BEAC (high-dose carmustine, etoposide, cytarabine, cyclophosphamide) and AHCT.

In the MCL2 and MCL3 cohorts, over a median follow-up of 9.2 years, the median overall survival (OS) and progression-free survival (PFS) were 12.5 years and 8.2 years, respectively (ranges not provided).

In this analysis, the researchers performed next-generation sequencing to determine the prognostic impact of common genomic alterations in MCL (including TP53 mutations and deletions, NOTCH1 mutations, CDKN2A deletions, and WHSC1 mutations), and the established prognostic indicators MCL International Prognostic Index (MIPI) score, Ki67 expression, and blastoid morphology.

CDKN2A deletions were the most commonly detected mutations (n=35/177; 20%), followed by TP53 deletions (n=29/176; 16%). Twenty patients had TP53 mutations, and nine patients carried both TP53 mutations and deletions.

In univariate analyses, TP53 deletions, CDKN2A deletions, TP53 mutations, and NOTCH1 mutations were each significantly associated with poorer outcomes. However, in multivariate analyses (conducted in 147 evaluable patients), only TP53 mutations remained statistically significantly associated with poorer OS and PFS:

  • hazard ratio (HR) for PFS = 6.2 (95% CI 2.6-14.9; p<0.0001)
  • HR for OS = 6.8 (95% CI 3.3-14.5; p<0.001)

Combined MIPI (MIPI-c) high-risk (defined as high-risk MIPI with Ki67 expression) was also significantly associated with poorer PFS and cumulative incidence of relapse (CIR; HR=2.2; 95% CI 1.2-4.0; p=0.01 for PFS and HR=2.6; 95% CI 1.4-4.9; p=0.003 for CIR).

When the authors compared outcomes between patients with (n=20) and without (n=156) TP53 mutations, they confirmed the poor prognosis conferred by TP53 mutations:

  • median OS: 1.8 years vs. not reached (p<0.001)
  • median PFS: 0.9 years vs. 10.2 years (p<0.001)
  • median time to relapse: 1.0 year vs. 12.3 years (p>0.001)

Compared with patients without TP53 mutations, patients with TP53-mutations “displayed highly aggressive baseline characteristics and were highly associated with blastoid morphology (12% vs. 60%; p<0.0001), Ki67 ≥30% (38% vs. 79%; p=0.001), MIPI high-risk (15% vs. 70%; p<0.001) and MIPI-c high-risk (9% vs. 58%; p<0.001),” the investigators observed.

TP53 mutations were also associated with lower rates of complete remission after induction chemotherapy (71% vs. 25%; p=0.0002) and AHCT (90% vs. 45%; p<0.0001).

In an editorial accompanying the report, Jonathon B. Cohen, MD, MS, from Winship Cancer Institute at Emory University, commented that these findings “contribute to the growing body of literature suggesting that available, aggressive induction therapies for MCL are highly effective for most, but not all, patients with MCL.”2

How to best manage these patients remains unknown, he continued, adding that “the answer will most likely reside with novel approaches to therapy.” Until these approaches are identified, he concluded, “assessing for TP53 aberrations should be considered a priority when only a limited panel of molecular assessments is feasible.”

The authors noted that the study’s findings may not be generalizable to patients treated with non-chemotherapeutic regimens.

Contributing authors report financial relationships with Celgene and Janssen.


References

  1. Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017 August 17. [Epub ahead of print]
  2. Cohen JB. TP53 mutations in MCL: more therapy is not better. Blood. 2017 August 17 [Epub ahead of print]

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