TP53-mutated MCL represents a phenotypically distinct and highly aggressive disease entity that responds poorly to high-dose strategies including rituximab, cytarabine, and ASCT

On 17^th August, in Blood, Christian W. Eskelund from Rigshospitalet, Copenhagen, Denmark, and colleagues published findings on common genomic alterations in Mantle Cell Lymphoma (MCL) and how they impact prognosis in two, large Nordic trials: MCL2 and MCL3 (NCT00514475).

Patients were aged 66 years or less, had stage II-IV disease, and were considered fit for Autologous Stem Cell Transplant (ASCT). The regimen used in the MCL2 and MCL3 trials included induction of alternating R-maxi-CHOP and R-high-dose-cytarabine, subsequently followed with BEAM or BEAC high-dose chemotherapy and ASCT. Overall, 320 patients were enrolled onto the two trials; one patient withdrew from the MCL2 trial because of a change in diagnosis.

Key Highlights:

Patients (n=319) and efficacy:

• Median age = 57 years (range, 29–65); male = 76%; MIPI intermediate- or high-risk = 51%; blastoid morphology = 18%; Ki67 ≥30% = 41%
• Median follow-up = 9.2 years
• Median OS = 12.5 years; median PFS = 8.2 years; 50% of pts had relapsed at 10.2 years
• Blastoid morphology, Ki67 ≥30%, and higher MIPI and MIPI-c risk groups significantly associated with poorer outcomes
• No differences in outcome observed between pts with or without Bone Marrow (BM) involvement

Genetic findings:

• DNA available for 191 pts; 183 samples were of sufficient quality for analysis
• CDKN2A deletions identified in 35/177 pts (20%); TP53 deletions identified in 29/176 pts (16%); both deletions identified in 12/176 pts (7%)
• Overall, 154 mutations were identified in 176 samples
• Most commonly mutated genes = ATM (27%), KMT2D (14%), TP53 (11%), and CCND1 (9%)
• At least one mutated gene was found in 90 pts (51%) and more than one mutated gene was found in 33 pts (19%)

Prognostic relevance of genetic aberrations:

• In multivariate analyses (n=147):
  • TP53 mutations (HR = 6.2, P < 0.0001) was an independent prognostic indicator for OS
  • For PFS and CIR, TP53 mutations (PFS: HR = 6.8, P < 0.0001; CIR: HR = 6.9, P < 0.0001) and high-risk MIPI-c (PFS: HR = 2.2, P = 0.01; CIR: HR = 2.6, P < 0.003) had significant prognostic impact
  • Combining TP53 mutations and deletions showed significant prognostic value for OS (HR = 3.1, P = 0.0004), PFS (HR = 2.8, P < 0.0001), and CIR (HR = 3.1, P < 0.0001)

Patients with mutated TP53:

• Stratifying pts by TP53 mutational status identified two cohorts of pts with different outcomes
• Median OS, median PFS, and median time to relapse in:
  • TP53 mutated pts: 1.8 years; 0.9 years; 1.0 year
  • TP53 unmutated pts: not reached; 10.2 years; 12.3 years
• Pts with one TP53 mutation = 19; pts with two TP53 mutations = 1
• Of the 21 mutations identified, 16 were missense mutations in the DNA binding domain
• TP53 mutated cases were highly aggressive and associated with blastoid morphology, Ki67 ≥30%, as well as high-risk MIPI and MIPI-c
• Significantly fewer TP53 mutated pts achieved CR after induction chemotherapy and ASCT
• Mutated TP53 associated significantly with MRD positivity pre- and post-ASCT
• One patient carried a mutation not previously reported to relate to hematological cancer in COSMIC or as a rare SNP (p.Pro191Arg [c.572C>G])

Patients with unmutated TP53:

• In the 156 TP53 unmutated cases, no other biomarker showed any prognostic value
• MIPI-c high-risk pts had a significantly shorter time to relapse versus MIPI-c non-high-risk pts (5.9 years vs 0 years; P = 0.035)

Overall, the authors stated that “TP53-mutated MCL represents a phenotypically distinct and highly aggressive disease entity”. Patients who harbor mutated TP53 have poor responses to high-dose regimens that include rituximab, cytarabine, and ASCT. The authors recommend stratifying patients by TP53 mutational status and should be studied separately in clinical trials that aim to explore novel targeted agents.

Abstract:

 Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable and we are still unable to identify patients who will not benefit from the current standard-of-care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger MCL patients from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%) were significantly associated with inferior outcomes (together with MIPI, MIPI-c, Blastoid morphology and Ki67>30%); however, in multivariate analyses only TP53 mutations (HR=6.2, p<0.0001) retained prognostic impact for overall survival (OS), while TP53 mutations (HR=6.9, p<0.0001) and MIPI-c high-risk (HR=2.6, p=0.003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome with a median OS of 1.8 years and 50% relapsed at 1.0 years (compared to not reached (NR) and 12.7 years, respectively, for TP53-unmutated cases, p<0.0001). TP53 mutations were significantly associated with Ki67>30%, blastoid morphology, MIPI high-risk and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab and autologous stem-cell transplant (ASCT). We suggest that MCL patients should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.