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Outcomes of Richter transformation
tion was an independent prognostic factor of RT survival.8 Four other studies did not test for TP53 somatic mutation and reported inconsistent results regarding the independ- ent prognostic role of del(17p).8,12,33,34 Given only 27 (13%) of our patients underwent the TP53 somatic mutation test, we likely underestimated the proportion of RT patients who had TP53 disruption, and thus might have underesti- mated the negative impact of this molecular abnormality on RT outcomes in our cohort.
The prognostic roles of COO, double expressor and double-hit status in de novo DLBCL have been well estab- lished.24-29 In this study, we found that these molecular markers were not prognostic for RT survival. Indeed, Eyre et al. showed that COO and Myc expression status did not influence RT survival in the O-CHOP trial,32 and Fidai et al. showed that MYC and/or BCL2 genetic alterations did not impact RT outcome in a retrospective study.33 RT and de novo DLBCL are likely different diseases given the known distinct genomic abnormalities,5,35 and the impacts of COO and double expressor/double-hit status may there- fore be different. We should note that molecular character- izations of COO and double expressor/double-hit status were incomplete in our dataset, and interpretation of these results should be made with caution.
In terms of other relevant prognostic factors, older age and elevated LDH were associated with worse OS in RT, consistent with the MD Anderson data.19 Clonal relationship between CLL and RT was reported to be a critical prognostic factor, with a much better outcome in clonally unrelated RT.8,36 Due to the difficulty of obtaining paired CLL and RT samples (at RT diagnosis) and a lack of universal assessment in our routine clinical practice, we only have a limited number of cases (<5%) in which the CLL and RT clonal relationship was reported. This diffi- culty is consistent with clinical experiences shared among several different academic centers. While we did not see a statistically significant association of clonal relationship with RT survival, this should not be taken as evidence that goes against prior studies. CLL IGHV mutation status was not associated with RT survival in our study. Prior studies were inconsistent regarding the prognostic role of CLL IGHV mutation in RT survival, with positive association reported in two studies (one in univariate analysis only, the other with only 16 RT patients)11,34 but not others.8,18 It remains unclear whether CLL IGHV mutation status is associated with RT outcome.
In our cohort, RT patients who were exposed to at least one novel agent (predominantly ibrutinib) for CLL treat- ment had a median OS of 10.9 months, similar to those whose CLL were treated with CIT only, and compares favorably to prior data.37-39 A number of studies have shown that RT that developed on novel agents had poor outcome, with a median OS of approximately 2-3.5 months if developed on ibrutinib37-39 and approximately 12 months if developed on venetoclax.40 In these studies, RT was primarily treated with R-CHOP- or R-EPOCH-like regimens. For our RT patients previously exposed to novel agents for CLL, approximately two-thirds were treated with novel agents (e.g. pembrolizumab, ibrutinib and venetoclax, etc.) and only one-third were treated with R- CHOP-like or other chemotherapy at first line. The effica- cy of novel agents in treating RT has been reported by a number of studies.41-46 For example, pembrolizumab demonstrated encouraging efficacy in patients with RT, particularly those with prior exposure of ibrutinib.43
Nivolumab in combination with ibrutinib and pem- brolizumab in combination with umbralisib and ublitux- imab also demonstrated encouraging activity in treating RT.45-47 In addition to the above studies, BTK inhibitors (NCT03899337), PI3K inhibitors (NCT03884998) and/or venetoclax (NCT03054896) based combination regimens (with or without chemotherapy) and other agents such as
Table 3. Median overall survival (OS) after Richter transformation (RT) diagnosis by clinical characteristics at RT diagnosis or first-line treat- ment approach for RT.
N
Prior CLL treatment
Untreated 69 Treated 135
Temporal relationship between
RT and untreated CLL
Concurrent CLL and RT 31 Sequential CLL and RT 38
Lines of prior CLL treatment
1 31
Median (95% CI) P <0.0001
46.3 (23.8-77.5) 7.8 (5.8-10.9)
0.25
0.09
0.07 13.3 (9.3-39.9)
11.3 (7.1-17.5)
39.9 (23.7-72.2)
6.2 (4.4-10.6)
0.13 14.6 (11.3-35.1)
8.0 (4.7-14.4)
12.8 (7.3-65.5)
8.3 (5.7-18.4)
0.89 12.8 (8.3-46.3)
10.6 (6.2-18.4)
34.0 (14.4-NE)
12.0 (8.0-65.5)
0.50 15.3 (7.4-122.8)
14.4 (6.2-NE)
13.3 (9.3-35.1)
14.4 (2.0-23.8)
0.08 15.3 (10.6-29.5)
14.6 (11.5-NE)
12.8 (3.2-NE) 10.9 (7.4-34.0) 6.1 (0.4-39.9)
66.9 (29.5-NE) 29.4 (13.7-111.6)
2 or more 104 Age at RT diagnosis (years)
15.3 (8.1-32.9)
5.8 (4.1-10.1)
≤65 69 >65 135
LDH
Normal 52
Del(17p)/TP53 mutation
No 86 Yes 45
IGHV mutation
Mutated 29 Unmutated 71
Cell of origin
GCB 31
Non-GCB 69
Myc/Bcl-2 double expressor
No 29 Yes 27
MYC/BCL2/BCL6 double-/triple-hit
No 58 Yes 8
First line treatment for RT
R-CHOP-like regimen1 114 Platinum or high dose cytarabine containing chemotherapy2 12 Other chemotherapy3 21 Novel agents4 19 Palliative therapy5 8
<0.001
Elevated 123
Bulky disease (≥ 5 cm)
No 63 Yes 62
0.046
0.74
0.61
1Premonidantly R-CHOP, small numbers of CHOP, MR-CHOP, lenalidomide-R-CHOP. 2R-ICE,(R-)DHAP,(R-)ESHAP, GDP, R-Hyper-CVAD,CODOX-M-IVAC,OFAR.3(R-)EPOCH- like,ProMACE-CytaBOM,infusional CDE,(R-)CEPP,R-CVP,R-bendamustine,R-gemc- itabine/prednisone, high-dose MTX-based. 4Ibrutinib, venetoclax, pembrolizumab, everolimus, CD19 antibody. 5Rituxiamab, obinutuzumab, corticosteroids, radiation therapy, alone or in combination. CLL: chronic lymphocytic leukemia; LDH: lactate dehydrogenase; IGHV: immunoglobulin heavy chain variable region; GCB: germinal center B-cell-like.
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