KMT2D Mutations Emerge as Negative Biomarker in MCL Based on MIPI-Genetic Prognostic Score

Simone Ferrero, MD

Simone Ferrero, MD

Target resequencing and DNA profiling of purified tumor samples collected from younger patients with mantle cell lymphoma (MCL) found that mutations ofKMT2Dand disruption ofTP53by deletion or mutation were associated with an increased risk of progression and death, both in univariate and multivariate analysis, from standard treatments, according to a study published recently inHaematologica.¹

Additionally, the authors, led by Simone Ferrero, MD, of the University of Torin in Italy, developed a new prognostic score known as the MIPI-genetic (MCL International Prognostic Index [MIPI]-g). They used the MIPI-g to identify a subgroup of patients who obtain little or no benefit from intensive chemoimmunotherapy. They then validated the prognostic score in an independent series of cases.

“Our study documents thatKMT2Dmutations are a novel, independent, adverse genetic biomarker in MCL, impacting both on PFS [progression-free survival] and OS [overall survival],” Ferrero et al wrote. “TP53aberrations (both mutations and deletion) prospectively confirm their adverse prognostic value in younger [patients with] MCL receiving high-dose chemoimmunotherapy followed by ASCT [autologous stem cell transplant], both in terms of PFS and OS…. Identification of eitherKMT2Dmutations orTP53disruption (or both) defines a high-risk group of young [patients with] MCL whose outcome is still not satisfactory despite intensive immune-chemotherapy and ASCT.”

The patients in the study were drawn from the Fondazione Italiana Linfomi (FIL) -MCL0208 trial.²This international, open-label, randomized, controlled phase III trial explored the efficacy of lenalidomide (Revlimid) as maintenance versus observation in patients with MCL. Patients in FIL-MCL0208 were young (18-65 years old) and fit with advanced disease (Ann Arbor stage II-IV) who had received first-line intensified and high-dose chemo-immunotherapy followed by ASCT.

Of the 300 FIL-MCL0208 participants, 189 (62%) provided CD19-positive sorted tumor cells from bone marrow that were evaluable for both mutations and copy number abnormalities to form the present study’s cohort. In this trial, PFS was the primary endpoint, while OS was one of several secondary outcomes.

The authors designed a targeted resequencing panel that included the coding exons and splice sites of 7 genes (ATM, TP53, CCND1, WHSC1, KMT2D, NOTCH1exon34, BIRC3) that are recurrently mutated in ≥5% of MCL tumors. They also includedTRAF2andCXCR4in the panel.

A large majority of patients (n = 130/186, 69.8%) had at least one somatic non-synonymous mutation that affected genes of the target region. The most commonly mutated gene wasATM(41.9%), followed byWHSC1(15.6%) andKMT2D(12.4%).KMT2Ddeletions occurred in 1.6% of patients (3/190) andTP53deletion in 13.2% patients (25/190).TP53was inactivated by mutations or deletions in 31/186 (16.6%) patients.

Ferrero et al found thatKMT2Dmutations were associated with poor clinical outcome in terms of both PFS and OS. At 4 years, the PFS rate inKMT2D-mutated patients was 33.2% versus 63.7% (P<.001) in wild-type cases, while the OS was 62.3% versus 86.8%, respectively (P= .002). Additionally, bothTP53mutations and deletion were associated with shorter PFS and OS rates at 4 years. When the outcomes data for patients withTP53mutations or deletions (n = 49/186, 26.3%) were grouped with those who hadKMTD2mutations, the 4-year PFS rate was 32.0% versus 69.9% of wild-type patients (P<.0001). The 4-year OS rate for this combined group was 65.1% versus 90.3% (P<.0001). No other investigated mutations showed a strong association with either PFS or OS.

Ferrero et al then assigned a score to the variables of MIPI-c class,TP53disruption andKMT2Dmutations. They integrated the clinical impact ofKMT2Dmutations andTP53disruptions into the MIPI-c prognostic index using the complete data that were available for 172 patients. They scored MIPI-c low, low-intermediate, and intermediate-high risk classes as 0 points. MIPI-c high-risk class scored 1 point, whileKMT2Dmutations as well asTP53disruptions scored 2 points.

They then grouped patients into 3 risk classes based on their total score to arrive at the MIPI-g index: 0 points, low-risk group; 1-2 points, intermediate-risk group; and&ge;3 points, high-risk group. The cohort contained 121 low-risk patients (70.3%), 38 intermediate-risk patients (22.1%), and 13 high-risk patients (7.6%).

The 4-year PFS rates for low-, intermediate-, and high-risk groups were 72.0%, 42.2%, and 11.5%, respectively (P<.0001). OS rates at 4 years stratified by risk group were 94.5%, 65.8%, and 44.9% (P<.0001), respectively.

Ferrero et al then used the raw sequencing data from the Nordic Lymphoma Group MCL2 and MCL3 phase II prospective trials to independently validate their findings.^3,4In the Nordic validation series,KMT2D-mutated patients showed a similar increased risk for OS, with a median OS of 12.7 years among wild-type patients compared to an OS of 8.4 years for patients with the mutation (95% CI, 0-17.6) for mutated cases. The Nordic validation series also replicated the MIPI-g score, with a median OS of 12.7 years for wild-type cases (95% CI not evaluable) and 2.0 years for patients with the mutation (95% CI, 1.2-2.8). The MIPI-g validation on the Nordic series showed similar results in the 4-year OS rates for low-risk patients (n = 103, 91.3%), intermediate-risk patients (n = 36, 72.2%) and high-risk (n = 13, 15.4%) MIPI-g groups.

Ferrero et al believe their study is the first to document the adverse impact ofKMT2Dmutations on cancer survival. &ldquo;Even thoughKMT2D-mutated patients of the FIL-MCL0208 trial scored in the higher MIPI-c risk classes, they did not show either elevated Ki-67 or blastoid morphology, suggesting thatKMT2Dmutations capture high-risk patients not otherwise identifiable through conventional pathologic parameters,&rdquo; they wrote.

The authors noted several important limitations, including the fact that their analyses were performed only on CD19-positive sorted bone marrow cells with no available tissue controls, possibly limiting the extrapolation of their results to lymph-node samples. Additionally, in noting that their validation relied on a limited number ofKMT2D-mutated patients, the Nordic trials are currently the only prospective studies with prompt available mutational data, adequate clinical follow-up, and similar characteristics.

References

1. Ferrero S, Rossi D, Rinaldi A, et al. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study. Haematologica [published online September 19, 2019]. doi: 10.3324/haematol.2018.214056.
2. Cortelazzo S, Martelli M, Ladetto M, et al. High Dose Sequential Chemotherapy with Rituximab and ASCT as First Line Therapy in Adult MCL Patients: Clinical and Molecular Response of the MCL0208 Trial, a FIL Study.Haematologica. 2015;100(s1):3-4.
3. 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;130(17):1903-1910. doi: 10.1182/blood-2017-04-779736.
4. Kolstad A, Pedersen LB, Eskelund CW, et al; Nordic Lymphoma Group. Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years.Biol Blood Marrow Transplant. 2017;23(3):428-435. doi: 10.1016/j.bbmt.2016.12.634.