Page 151 - Haematologica May 2022

DA-EPOCH-R in double expressor lymphoma
Table 4. Results of the multivariable Cox models for progression-free and overall survival.
Model
Rearrangements DEL-BCL2 vs. DEL DEL-MYC vs. DEL** DEL-DH/TH vs. DEL
TP53 mutation
Mutated vs. wild-type
Not performed vs. wild-type
International prognostic index 0-2 vs. 3-5
Systemic CNS therapy
None vs. intravenous MTX Intrathecal MTX vs. intravenous MTX
Staging
III-IV vs. I-II
Sex
Female vs. male
Age*** 65 vs. 49
Progression-free survival
Overall survival
Hazard ratio (95% CI)
1.49 (0.48; 4.64)
-
1.15 (0.46; 2.87)
3.13 (1.04; 9.40) 0.98 (0.41; 2.35)
0.36 (0.12; 1.06)
3.74 (1.22; 11.41) 1.99 (0.83; 4.76)
1.19 (0.21; 6.69)
0.36 (0.14; 0.98)
-
P* 0.880
0.072
0.063 0.062
0.847 0.045 -
Hazard ratio (95% CI)
0.16 (0.02; 1.48)
-
1.00 (0.37; 2.75)
8.90 (2.14; 36.99) 0.75 (0.22; 2.53)
0.18 (0.04; 7.4)
8.49 (1.82; 39.57) 4.25 (1.2; 15.02)
-
-
1.52 (0.51; 4.56)
P* 0.408
0.002
0.018 0.019
-
-
0.752
CI: confidence interval; DEL: double expressor lymphomas; DH/TH: double-hit/triple-hit; CNS: central nervous system; MTX, methotrexate. *Wald test P-value; **No survival or progression events observed; ***Modeled as restricted cubic spline and reporting result of 65 vs. 49 years comparison.
therapies (n=2 auto-stem cell transplantation [auto-SCT], n=2 allo-SCT, n=1 lenalidomide in combination with radiotherapy).
Central nervous system prophylaxis and central nervous system relapse
At diagnosis, only two patients had cerebrospinal fluid involvement: one died early of systemic progressive disease and the other is still alive after therapy including high-dose methotrexate.
The CNS prophylaxis was chosen at the discretion of the treating physician. Sixty-six (54%) patients received sys- temic HD-MTX, 40 (33%) underwent intrathecal chemotherapy with methotrexate and cytarabine and 16 (13%) did not receive any CNS prophylaxis at all. In partic- ular, patients not receiving CNS prophylaxis had less extra- nodal involvement at risk for CNS relapse. All characteris- tics are detailed in the Online Supplementary Table S5.
Systemic methotrexate-based CNS prophylaxis con- ferred a better 2-year OS (94%, [range, 88-100%]) as com- pared to intrathecal or no CNS prophylaxis (75%, [range, 63-91%] and 65%, [range, 42-100%] respectively; P=0.008) (Figure 2C and D). A significant advantage in OS was observed even after exclusion of DH/TH patients (2-year percentage OS 96% vs. 81%, vs. 63%, respectively, [P<0.001; Figure 2E and F]) that was the subgroup with the worst outcome.
Overall, we observed five CNS relapses, and the cumula- tive incidence of relapse at 1- and 2-year was 2% (range, 1- 9%) and 5% (range, 2-13%) respectively in the entire cohort. All patients with CNS relapse were DEL only, all but one were non-GCB. Four of five patients died of CNS lymphomas. The CNS relapse occurred even in patients who received CNS prophylaxis (3 of 5 patients) and in four out five with low CNS-IPI.
Discussion
In the present retrospective study, we collected a large number of consecutive DEL patients (n=122) who were treated with the DA-EPOCH-R regimen to test the hypothesis that an intensive regimen could overcome poor clinical, and biological prognostic factors. To the best of our knowledge, this study includes the largest series of DEL patients exposed to an intensified regimen. All DEL patients were analyzed for MYC and/or BCL2 rearrange- ments and, partly, for TP53 mutational status. Indeed, the 2-year PFS and OS of 74% and 84%, respectively, for the entire cohort seem promising. Further, in patients charac- terized by IPI score of 3-5, the results are comparable to those achieved with other intensified treatments (R-CODOX/IVAC and R-ACVB).23,24
Currently, the treatment of DEL without any gene rearrangement remains an unmet clinical need. The phase III trial performed by the Alliance group comparing the R- CHOP and DA-EPOCH-R regimens in newly diagnosed DLBCL included only a limited number of DEL, thus pre- venting the possibility of drawing definitive conclusions on the role of DA-EPOCH-R in this subtype.25 Our series of 81 DEL patients without any rearrangement showed a 2-year PFS and OS of 75% and 86%, respectively, suggest- ing a potential role of the intensive regimen. Recently, Morschhauser et al. evaluated the combination of veneto- clax with standard R-CHOP or obinutuzumab-CHOP in DEL patients or those with high expression of BCL2, showing a similar 2-year PFS of 72% and 77%, respective- ly.
Patients with a DEL-DH/TH status showed mainly an intermediate and high-risk IPI (75%) and had a trend for inferior OS at 2 years (66%) as compared to DEL only (86%), whereas the observed 2-year PFS of 63% was not
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