Page 252 - Haematologica March 2020

Y. Wang et al.
appears to be associated with relative long-term survival in select cases.19-23 Overall, RT has a poor prognosis, with a median survival of only 1-2 years.3,5
The landscape of CLL management has changed dra- matically with the emergence of several novel targeted agents, such as Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib, phosphoinositide 3-kinase δ (PI3Kδ ) inhibitors idelalisib and duvelisib, and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. It is unclear whether these novel agents affect the risk, prognosis and management of RT. In de novo DLBCL, the prognostic roles of cell of origin (COO), Myc and Bcl-2 double expression, and MYC, BCL2 and/or BCL6 gene rearrangements have been well recognized.24-29 However, the potential impact of these molecular markers on the outcome of DLBCL-type RT has not been well studied.
In this study, we report the clinical characteristics, treat- ment pattern, and outcomes of a large series of RT patients (n=204) from a single center over more than two decades including the era of novel agents (from 2012 to the present). The potential prognostic impact of prior CLL treatment as well as CLL- and RT-related molecular mark- ers were also explored.
Methods
Patients
This study was approved by the Mayo Clinic Institutional Review Board. All patients were identified from the Mayo Clinic CLL database which includes consecutive CLL patients evaluat- ed in the Division of Hematology at Mayo Clinic, Rochester, MN, USA.2,30,31 CLL patients who developed biopsy-proven RT between April 1993 and April 2018 were identified from the database. For this study, the focus was RT to DLBCL (including high grade B-cell lymphoma, such as double-/triple-hit lym- phoma which is now known as high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements); transforma- tions to Hodgkin lymphoma or other histology were excluded. Clinical, pathological, and molecular characteristics [IGHV mutation, CLL fluorescence in situ hybridization (FISH)] and all treatment information during the CLL phase were abstracted from the database. Clinical, pathological and molecular charac- teristics [CLL FISH, TP53 somatic mutation, COO by Hans algo- rithm, Myc/Bcl-2 expression by immunohistochemistry (IHC), MYC/BCL2/BCL6 rearrangement by FISH, CLL and RT clonal relationship by immunoglobulin gene rearrangement], treatment course, clinical response to treatment as determined by treating physician, and survival information after RT was abstracted by chart review. On IHC, the cut-off value for positivity was 40% for Myc, and 50% for Bcl-2. Our institution started to routinely test for Myc expression by IHC and MYC rearrangement by FISH in all DLBCL cases in 2012; therefore, we have missing information on IHC as well as FISH results in patients diagnosed with RT prior to this.
Statistical analysis
The date of RT diagnosis was defined as the date of the biop- sy which led to the pathological diagnosis of RT. The time to transformation was defined as the time from CLL diagnosis to RT diagnosis. Overall survival (OS) was defined as the time from RT diagnosis to death from any cause. Time-to-event data were analyzed using the Kaplan-Meier method. Cox proportional hazards models were used to analyze associations between OS and various factors. P<0.05 was considered statistically signifi-
Table 1. Clinical characteristics at Richter transformation diagnosis in 204 patients.
Number (n=204) %
Year of RT diagnosis
Prior to 2002
2002-2011 70 34.3 2012-2018 101 49.5
Age (years)
Median (range) ≤65
>65
Time to transformation (years) Median (range)
Prior CLL treatment
69 (30-88)
69 33.8
135 66.2 4.7 (0.0-34.5)
33 16.2
Untreated 69 33.8
Treated with CIT only
Treated with at least one novel agent Lines of prior CLL therapies
Missing
PET SUVmax (n=69)
Median (range)
LDH (IU/L) (n=175)
Median (range) Ki-67 (n=55)
Median
Pathology at transformation
DLBCL
High grade B-cell lymphoma Cell of origin
GCB Non-GCB Missing
Myc IHC
Negative Positive (≥40%) Missing
Bcl-2 IHC Negative Positive (≥50%) Missing
Double expressor
Negative Positive Missing MYC FISH Negative Positive Missing
108 52.9
79
13.9 (2.9-30.0) 306 (99-9000) 80% (10-100%)
193 94.6
11 5.4
31 31.0 69 69.0
104
12 27.9 31 72.1
161
20 19.4 83 80.6
101
29 51.8 27 48.2
148
50 73.5 18 26.5
136
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Median (range)
27 13.2 2 (0-13)
Bulky disease (≥5 cm)
No 63 50.4 Yes 62 49.6
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