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MYD88 mutational status improves classification and prognostication in DLBCL
Table 3A. Prognostic impact of molecular aberrations and IPI risk factors on overall survival: univariable and multivariable analysis.
Univariable
HR 95%-CI
1.37 0.91-2.07
2.33 1.41-3.85 8.15 5.23-12.7
1.54 1.00-2.37 1.53 1.01-2.31
1.62 0.88-3.00 0.74 0.37-1.47
1.21 0.71-2.04 1.54 0.86-2.78 1.43 0.81-2.53 1.64 1.08-2.48
Overall survival
Multivariable Model 1 (IPI)
Multivariable Model 2 Multivariable Model 3 (IPI + molecular aberrations (IPI + molecular aberrations
IPI: >2 Extranodal Yes (vs. No)
IPI: Stage
III/IV (vs. I/II)
IPI: ECOG Performance Score
>2 (vs. <1) IPI: Age
>60 (vs. <60) IPI: LDH
>Upper limit (vs. Normal) MYC
Rearranged
(vs. Wildtype) BCL2
Rearranged
(vs. Wildtype) BCL6
Rearranged
(vs. Wildtype) EBV Status
Positive (vs. Negative) CD79B
Mutated (vs. Wildtype) MYD88
Mutated (vs. Wildtype) Cross-validated C-index
95%-CI
0.90-2.22
0.98-2.84
4.67-12.15 1.35 0.85-2.13 1.14 0.74-1.77
HR
1.49
1.71
8.69
1.38 1.15
1.71 0.51
0.94 1.29
95%-CI
0.94-2.37
0.97-3.00
5.23-14.45 0.87-2.19 0.73-1.81
0.89-3.27 0.24-1.08
0.53-1.65 0.67-2.47
HR
1.71
1.84
8.16
1.33 1.29
1.86 0.57
1.00 1.65 0.76 1.87
95%-CI
1.07-2.74
1.04-3.25
4.90-13.59 0.83-2.12 0.82-2.05
0.93-3.69 0.26-1.24
0.55-1.83 0.82-3.30 0.38-1.49 1.10-3.20
HR
1.41
1.67
WHO 2016)
WHO 2016 + MYD88 + CD79B)
7.53
0.6
0.69
0.70
For the multivariable model,unknown was regarded as a separate category for these variables for which some data were missing (not reported).
were 37.2% (95%-CI 31.2-43.3) and 10.1% (95%-CI 6.4- 13.9), respectively. Figure 3 shows the survival outcomes presented for the anatomical location, IPI-score, and MYD88 status. The survival outcomes of COO and the other aberrations are outlined in the Online Supplementary Figure S2 (none of these factors had a significant impact).
The IPI clearly predicted OS (Figure 3): patients with IPI scores of 0/1, 2/3, and 4/5 had an OS of 84.9% (95%-CI 76.3-94.5), 58.0% (95%-CI 50.3-66.8), and 34.4% (95%- CI 21.3-55.5), respectively. IPI also showed a significant difference in cumulative incidences of relapses (Gray’s; P=0.025) and non-relapse mortality (Gray’s; P=0.006). In addition to the IPI, DLBCL with IP locations had inferior outcomes (OS 47.1%, 95%-CI 36.5-60.9; PFS 41.0%, 95%-CI 30.7-54.9) compared to nodal (OS 71.2%, 95%- CI 61.4-82.4; PFS 55.7%, 95%-CI 45.3-68.6) and other extranodal sites (OS 62.6%, 95%-CI 53.9-72.7; PFS 58.1%, 95%-CI 49.4-68.2) (log-rank; P=0.004 and P=0.024). This unfavorable prognosis was particularly associated with the CNS location. Within the IP group, patients with CNS location had a significantly inferior 5- year OS of 29.9% (95%-CI 17.7-50.5) compared to 65.5% (95%-CI 50.9-84.3%) for PTL (log-rank; P=0.003).
With respect to the molecular markers, patients with- out any detected aberrancy demonstrated a good-risk pro- file with a superior OS (78.0%, 95%-CI 67.2-90.4, versus 56.3%, 95%-CI:48.6-65.2; Figure 2B) (log-rank; P=0.010) and PFS (65.4%, 95%-CI 53.2-80.3, versus 48.2%, 95%-CI 40.6-57.3; Figure 2C) (log-rank; P=0.031) compared to patients who had one or more aberration(s). The cumula- tive incidence of relapse/progression for this good-risk profile was 28.6% (95%-CI 15.8-41.4) compared to 39.3% (95%-CI 31.2-47.4) (Gray’s; P=0.155). This good risk pro- file included patients with a lower ECOG-PS, age<60 years, and more GCB subtypes (Chi square; P=0.012, P=0.001, and P=0.006, respectively) compared to patients with one or more aberrations. Patients in the good risk category seem to be susceptible for immune-chemothera- py with enduring responses, however, the molecular background of this subgroup remains unknown. In IP-DLBCL, a total of 93.8% of the patients were classified in the risk group with ≥1 aberrations.
MYD88-mutated DLBCLs had a significantly inferior 5-year OS compared to DLBCL with wild-type MYD88 (log-rank; P=0.019; HR 1.64, 95%-CI 1.08-2.48) and signif- icantly inferior 5-year PFS (log-rank; P=0.049; HR 1.46,
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