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Outcomes of Richter transformation
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alone), and 2 other patients developed RT on frontline ibrutinib. Median lines of CLL therapy prior to RT was 2 (range 0-13).
Thirty-three patients were diagnosed with RT prior to 2002 (when rituximab was not routinely available), 70 patients were diagnosed between 2002 and 2011, and 101 patients were diagnosed in 2012 or later (when ibrutinib had become available). The median age at RT diagnosis was 69 years (range 30-88). Sixty-two (49.6%) of 125 patients had bulky disease (≥ 5 cm). COO by Hans algo- rithm was germinal center B-cell-like (GCB) and non-GCB in 31 of 100 (31.0%) and 69 of 100 (69.0%) patients, respectively. Myc and Bcl-2 were positive by IHC in 31 of 43 (72.1%) and 83 of 103 (80.6%) cases, respectively; 27 of 56 (48.2%) were double-expressors. MYC, BCL2, and BCL6 rearrangement was positive by FISH in 18 of 68 (26.5%), 10 of 34 (29.4%), and 4 of 31 (12.9%) cases, respectively; 8 of 66 (12.1%) were double-/triple-hit. Forty-five (34.4%) of 131 patients had del(17p) or TP53 mutation, i.e. TP53 disruption. CLL and RT were clonally unrelated in 9 (42.9%) of 21 patients.
Richter transformation treatment and outcome
Pattern of first-line treatment for RT is shown in Table 2. The most commonly used first-line treatment was an R-CHOP-like regimen (n=114, 65.5%). Twelve (6.9%) patients received platinum or high-dose cytarabine con- taining chemotherapy; 21 (12.1%) patients received other chemotherapy (6 with DA-EPOCH-R-like regimen, 15 with others including ProMACE-CytaBOM, R-CEPP, infu- sional CDE, R-CVP, R-bendamustine, R-gemcitabine/prednisone, high dose methotrexate-based regimen). Nineteen (10.9%) patients received novel agents: ibrutinib (n=4), venetoclax (n=1), ibrutinib plus venetoclax (n=3), pembrolizumab (n=7), pembrolizumab plus ibrutinib (n=1), CD19 monoclonal antibody (n=1), everolimus (n=1), everolimus plus panobinostat (n=1). Eight (4.6%) patients received palliative therapy defined as rituximab, corticosteroids, radiation therapy, alone or in combination.
Clinical response (assessed by treating physician) to first-line treatment was complete response (CR) in 54 (36.0%), partial response (PR) in 37 (24.0%), stable disease (SD) in 18 (12.0%), and progressive disease (PD) in 42 (28.0%) of 150 patients. The median follow up after RT was 67.0 months, and there were a total of 150 deaths. The median OS after RT diagnosis was 12.0 months (Figure 1A).
Survival by clinical and molecular factors and treatment is summarized in Table 3. The median OS was significant- ly better in patients who received no CLL treatment than those who received any CLL treatment, with a median OS of 46.3 versus 7.8 months (P<0.001) (Figure 1B). Among the 69 patients who received no CLL treatment, 31 had con- current CLL and RT (i.e. RT diagnosis within 3 months of CLL diagnosis), with a median OS of 66.9 months; in the other 38 patients with sequential CLL and RT (median time to transformation 55.5 months), the median OS was 29.4 months (P=0.25) (Figure 1C). Among the 135 patients who had received treatment for CLL, patients with only one line of CLL treatment (n=31) had a trend of better OS compared to those with two or more lines of CLL treat- ment (n=104), with a median OS of 15.3 versus 5.8 months (P=0.09) (Figure 1D). Patients who received CIT only and those who received at least one novel agent for CLL had a
BCL2 FISH
Negative
Positive
Missing 170 BCL6 FISH
24 70.6 10 29.4
Negative
Positive
Missing 173
Double-/triple-hit
No
Yes
Missing 138
27 87.1 4 12.9
58 87.9 8 12.1
EBV
Negative
Positive
Missing 152
38 73.1 14 26.9
Del(17p) or TP53 mutation Negative
Positive
Missing
CLL and RT clonal relationship Unrelated
Related
Missing
86 65.6 45 34.4 73
9 42.9 12 57.1
180
RT: Richter transformation; CLL: chronic lymphocytic leukemia; PET: positron emis- sion tomography; SUV: standardized uptake value; LDH: lactate dehydrogenase; DLBCL: diffuse large B-cell lymphoma; GCB: germinal center B-cell-like; IHC: immuno- histochemistry; FISH: fluorescence in situ hybridization; EBV: Epstein-Barr virus.
cant. All statistical analyses were carried out in SAS 9.4 (SAS Institute, Cary, NC, USA).
Results
Clinical characteristics in the chronic lymphocytic leukemia phase
A total of 204 patients with CLL who developed RT were identified. Baseline characteristics at CLL diagnosis are shown in Online Supplementary Table S1. The median age at CLL diagnosis was 62 years (range 22-85), and 148 (72.5%) were male. Seventy-one (71.0%) of 100 patients tested had unmutated IGHV. CLL FISH detected del(17p) in 33 (25.4%), del(11q) in 18 (13.8%), and trisomy 12 in 19 (14.6%) of 130 patients. Forty-seven (66.2%) of 71 patients were high or very high risk by CLL-IPI score (≥4).
Clinical characteristics at Richter transofrmation diagnosis
Median time to transformation was 4.7 years (range 0- 34.5) (Table 1). Prior to RT, 69 (33.8%) patients received no treatment for CLL, 108 (52.9%) received chemoim- munotherapy (CIT) only, and 27 (13.2%) received at least one novel agent (idelalisib, ibrutinib, or venetoclax) for CLL; 19 patients received CIT previously and developed RT on novel agents (17 ibrutinib, 1 idelalisib, 1 veneto- clax), 6 patients received novel agents previously and developed RT on subsequent treatment (1 rituximab-ben- damustine, 3 rituximab-corticosteroid, and 2 rituximab
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