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Letters to the Editor
increase of the WBC count was observed (Figure 2B). The hemorrhage resolved with supportive care, and ibrutinib was restarted, with stabilization of the WBC count. Three weeks later the patient died due to secondary bac- terial pneumonia.
Despite high tumor burden neither patient showed signs of tumor lysis syndrome. In both patients, interrup- tion of ibrutinib was associated with an increase of WBC count that declined (patient A) or stabilized (patient B) when ibrutinib was re-introduced. The clinical course of both patients was complicated by severe bacterial pneu- monia which eventually led to treatment termination. The combination of venetoclax and ibrutinib had a toler- able safety profile but was associated with increased fre- quencies of neutropenia and respiratory infections in studies including patients with other hematologic dis- eases such as mantle cell lymphoma or chronic lympho- cytic leukemia.10,11 Both patients we treated had received alemtuzumab treatment as a re-induction attempt and experienced increased neutrophil counts (Online Supplementary Figure S3A and B). Thus, it is plausible that prior anti-CD52 could increase infectious complications of the combination.
In vivo dynamic BH3-profiling with samples from the two patients while on treatment showed a modest increase in overall apoptotic priming by ibrutinib, driven by an enhanced dependence on Bcl-2. This effect was fur- ther enhanced by venetoclax (Figure 2C and D), which is consistent with our in vitro data on T-PLL samples (Figure 1F). Immunoblotting analysis demonstrated that veneto- clax treatment alone led to the induction of both phos- phorylated and total ITK, an effect that was abrogated by the addition of ibrutinib as demonstrated in samples of patient A while on treatment (Figure 2E). In patient B, treatment with venetoclax was started 1 day after ibruti- nib. ITK activity (phospho-ITK) decreased during treat- ment and regained activity upon interruption of ibrutinib treatment (Figure 2F). Intracellular T-cell receptor signal- ing via increased phospho-ITK expression is known to be associated with inferior prognosis in T-cell lymphomas, and ITK inhibition has been shown to prime apoptosis of malignant T cells by downregulating anti-apoptotic pro- teins, including Bcl-2, MCL-1, and Bcl-XL.12 At the pro- tein level, in patient A expression of Mcl-1 and Bcl-2 was induced during venetoclax monotherapy, but was reduced upon combinatorial treatment. In contrast, patient B showed a predominant induction of pro-apop- totic BH3 family members in response to combined ibru- tinib and venetoclax treatment (Online Supplementary Figure S3C and D). However, previous research has shown that immunoblotting does not accurately reflect the clinical efficacy of BH3 mimetics.9 Our previous report and data presented here suggest that exposure to venetoclax monotherapy leads to ITK activation and increased Bcl-2 and Mcl-1 expression, and Bcl-2 depend- ence with a suboptimal clinical response.4 Co-treatment with venetoclax plus ibrutinib may reduce ITK activity, increase Bcl-2 dependence, and restore susceptibility to venetoclax (Figure 2G). Similarly, Mcl-1 inhibition has been shown to act synergistically with venetoclax in T-PLL cells.13
Our high-throughput screen identified ibrutinib as a synergistic combination partner for venetoclax in T-PLL. In this study, we favored synergy over potency, since we hypothesized that synergism would be associated with a more favorable clinical safety profile. Indeed, the combi- nation of venetoclax and ibrutinib has been considered safe in other indications.10,11 We acknowledge strong sin- gle-agent potency of other compounds such as the his-
tone deacetylase inhibitor, panobinostat; however the added effect of its combination to venetoclax was negli- gible (Online Supplementary Figure S1B).
Recently, anecdotal cases of venetoclax combinatorial treatments of T-PLL patients have been published: In line with our findings Oberbeck et al. reported disease stabi- lization after short-term treatment of one patient with venetoclax plus ibrutinib, but progression after cessation of treatment.14 Alfayez et al. treated one patient with venetoclax plus pentostatin who achieved complete remission for 10 months.15 This combination, however, did not demonstrate synergism in our screen (Figure 1B), but future studies could determine a putative benefit for T-PLL patients.
Our in vitro studies demonstrated that the combination of venetoclax and ibrutinib increased T-PLL cell priming for apoptosis and Bcl-2 dependence. The combination produced clinical responses in two heavily pretreated patients with r/r-T-PLL and enhanced Bcl2-dependence in-vivo while reducing ITK activity. These results prompt- ed the initiation of the first international multicenter clin- ical study in T-PLL, the phase II VIT-trial (NCT03873493) testing the combination of venetoclax and ibrutinib in r/r- T-PLL in a larger cohort of patients.
Christoph Kornauth,1 Charles Herbaux,2 Bernd Boidol,3 Chantal Guillemette,4 Patrick Caron,4 Marius E. Mayerhöfer,5 Stéphanie Poulain,6 Olivier Tournilhac,7 Tea Pemovska,1 Stephen J.F. Chong,2 Emiel van der Kouwe,1 Lukas Kazianka,1 Georg Hopfinger,8 Daniel Heintel,9 Roland Jäger,10
Markus Raderer,11 Ulrich Jäger,1 Ingrid Simonitsch-Klupp,12 Wolfgang R. Sperr,1 Stefan Kubicek,3 Matthew S. Davids2# and Philipp B. Staber1#
#MSD and PBS contributed equally as co-senior authors.
1Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; 2Department of Medical Oncology, Dana-Faber Cancer Institute, Harvard Medical School, Boston, MA, USA; 3Center for Molecular Medicine (CeMM), Austrian Academy of Sciences, Vienna, Austria; 4Centre Hospitalier Universitaire de Québec – Université Laval and Faculty of Pharmacy, Université Laval, Québec, Canada; 5Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria; 6UMR CANTHER, INSERM 1277-CNRS 9020 UMRS 12, University of Lille, Hematology Laboratory, Biology and Pathology Center, CHU de Lille, Lille, France; 7Service d'Hematologie Clinique et de Therapie Cellulaire, CHU, Universite Clermont Auvergne, EA7453 CHELTER, CIC1405, Clermont Ferrand, France; 83rd Medical Department, Centre for Oncology and Haematology, Kaiser Franz Josef-Spital, Vienna Austria; 91st Austria Medical Department, Center for Oncology and Hematology, Wilhelminenhospital Vienna, Vienna, Austria; 10Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria; 11Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria and 12Clinical Department of Pathology, Medical University of Vienna, Vienna, Austria
Correspondence: PHILIPP B. STABER philipp.staber@meduniwien.ac.at
doi:10.3324/haematol.2020.271304 Received: September 8, 2020. Accepted: February 11, 2021. Pre-published: February 25, 2021.
Disclosures: UJ and PBS have received honoraria and advisory board fees from Abbvie and Janssen. MSD has provided consultancy or scientific advisory board services for AbbVie, Adaptive Biotechnologies, Ascentage, AstraZeneca, Beigene, Celgene,
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