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Y. Wang et al.
immunomodulatory drug lenalidomide (NCT03113695, NCT02005289), engineered anti-CD19 monoclonal anti- body MOR208 (NCT02005289), and CD3/CD19 bispecif- ic antibody blinatumumab (NCT03121534, NCT03931642) are actively being tested in clinical trials for RT. Chimeric antigen receptor (CAR) T cells are also showing promise in improving the outcome of RT48 and are further tested in clinical trials (NCT03484702). Taken together, novel agents (e.g. pembrolizumab/nivolumab, ibrutinib and venetoclax) would seem to be very reason- able choices in patients who develop RT while receiving one of the targeted agents (e.g. ibrutinib, venetoclax, ide- lalisib) for CLL. However, it is important to note that despite promising results from multiple studies,41-48 further improvements to increase the efficacy and select optimal patients for different novel agents are clearly needed.
Patients who underwent SCT (n=24, 11.8%) in our cohort overall had a favorable outcome, with a median post-SCT survival of 55.4 months. The role of SCT in RT management has been explored previously.19-22 In the MD Anderson cohort, 20 (13.5%) of 148 RT patients were able to proceed to SCT (3 autologous, 17 allogeneic), and seven patients who underwent allogeneic SCT for consolidation had a favorable outcome with a 3-year OS of 75%.19 A ret- rospective study by the European Group for Blood and Marrow Transplantation (EBMT) showed that post-remis- sion SCT may benefit a subset of RT patients, with a 3-year OS of 59% for autologous SCT and 36% for allo- geneic SCT.20 Two recent single institution studies also reported somewhat favorable outcome of allogenic SCT in RT patients, with a 2-year OS of 44% in one study and a 4-year OS of 50% in the other.21,22 Collectively, these data suggest that select RT patients can benefit from SCT. One should be aware of the potential selection bias when interpreting the data, e.g. patients need to be relatively young and in good condition to proceed to SCT. For example, 10 of the 24 patients in our SCT cohort received no prior CLL treatment; patients were relatively younger, and most patients achieved a favorable response with 1-2 lines of RT therapy and then went on to SCT. We used substantially more autologous (n=20) than allogeneic
(n=4) SCT. While allogeneic SCT target both the CLL and RT clones, an autologous SCT primarily eradicates the RT clone and spares the undesired high non-relapse mortality associated with allogeneic SCT.
Our study shows that RT has poor clinical outcomes in general. However, as a heterogeneous disease, its outcome is influenced significantly by prior CLL therapy status. One reason for the poor survival observed in RT after prior CLL therapy may be the known potential of CLL clones to undergo clonal evolution under the pressure of therapy.49,50 We propose a newer approach to manage RT based on their prior CLL therapy status. In treatment- naïve patients and patients with clonally unrelated DLBCL, immunochemotherapy, in particular R-CHOP- like regimens, is the preferred approach in treating these RT. In patients exposed to targeted CLL therapies (includ- ing kinase inhibitors and BCL-2 inhibitor) or prior chemoimmunotherapies, the management of RT would likely need to incorporate novel agents, immunotherapy, and/or cellular therapy in clinical trials. SCT consolidation should still be considered in RT patients who achieve a good response to therapy. We fully expect that RT biology will continue to evolve with the changing landscape of CLL as management with novel agents are robustly mov- ing to the front line. In support of this, recent data indicat- ed that 70-80% of RT that developed on novel agents had TP53 disruption and/or complex karyotypes, both of which were prognostic of poor outcomes in RT.39 It is hoped that our study can provide more valuable informa- tion on current management of RT and also point to areas of interest for future clinical trials and biological studies.
Funding
This study was supported by grants from the National Institute of Health Lymphoma SPORE CA 97274 and K23 CA160345, K12 CA090628, Richard M. Schulze Family Foundation for Awards in Cancer Research, the Fraternal Order of Eagles Cancer Research Fund, and the Predolin Foundation. SAP and SSK are recipients of the K12 CA090628 grant from the National Cancer Institute (Paul Calabresi Career Development Award for Clinical Oncology).
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