The Combination of Venetoclax and Ibrutinib Is Effective in Relapsed/Refractory T‐prolymphocytic Leukemia and Influences Bcl‐2‐family Member Dependencies

Kornauth, Christoph; Herbaux, Charles; Boidol, Bernd; Guillemette, Christine; Mayerhöfer, M.E.; Jäger, Uli; Kubicek, Stefan; Davids, Matthew S.; Staber, Philipp B.

doi:10.1002/hon.161_2631

Cited by 8 publications

(11 citation statements)

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“…This corroborates data by us and others, in which single-agent ITK inhibitors led to a diminished activation upon T cell receptor (TCR) stimulation, but did not affect viability of T-PLL cells [62,63]. Two r/r T-PLL patients treated with the combination of venetoclax and ibrutinib showed substantial clinical responses [61]. Based on these pilot data, an international study evaluating the efficiency of venetoclax plus ibrutinib in alemtuzumab r/r T-PLL was initiated and is currently recruiting (VIT trial, NCT03873493).…”

Section: Antagonists Of Bcl2 Family Moleculessupporting

confidence: 91%

“…Aiming at identifying potentially synergistic partners, a combination screen identified ibrutinib (inhibitor of IL-2 inducible T cell kinase, ITK) as a suitable co-treatment. This was underlined by an increase of BCL2 dependence after ibrutinib priming, the latter having no effect on T-PLL cell viability [61]. This corroborates data by us and others, in which single-agent ITK inhibitors led to a diminished activation upon T cell receptor (TCR) stimulation, but did not affect viability of T-PLL cells [62,63].…”

Section: Antagonists Of Bcl2 Family Moleculessupporting

confidence: 86%

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Advances and Perspectives in the Treatment of T-PLL

Braun

Jan

Wahnschaffe

et al. 2020

Curr Hematol Malig Rep

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Purpose of Review T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumabbased induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies. Recent Findings Alemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CART cell therapy are at the stage of pre-clinical assessments of activity and feasibility. Summary The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-inhuman results in T-PLL, and urgently have to be transferred to systematic clinical testing.

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Section: Antagonists Of Bcl2 Family Moleculessupporting

confidence: 91%

Section: Antagonists Of Bcl2 Family Moleculessupporting

confidence: 86%

Advances and Perspectives in the Treatment of T-PLL

Braun

Jan

Wahnschaffe

et al. 2020

Curr Hematol Malig Rep

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“…The patient presented in poor general condition (ECOG‐2) and required immediate cytoreductive treatment because of transfusion‐dependent anemia and thrombocytopenia caused by rapid progression of T‐PLL. Since flow cytometry demonstrated lack of CD52 expression on the surface of the leukemic cells, combined treatment with ibrutinib and venetoclax was initiated according to a recently published protocol 21 . Treatment was initially well tolerated without evidence of tumor lysis and effective as indicated by a rapid decline of T‐PLL cells in the peripheral blood within the first 72 hours of treatment (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

“…As reports from the literature indicated that down‐reguIation of CD52 counteracts the anti‐leukemic effects of anti‐CD52 antibodies, 6,7,23 we refrained from retreating patient 12 with alemtuzumab. Following a recently published investigational protocol, 21 combination therapy with ibrutinib and venetoclax was initiated resulting in rapid decline of T‐PLL cells in the peripheral blood within the first 72 hours of treatment. This latter observation is clinically important, since until now efficacy data regarding combined application of ibrutinib and venetoclax in T‐PLL patients are scarce.…”

Section: Discussionmentioning

confidence: 99%

Mutations in PIGA cause a CD52‐/GPI‐anchor‐deficient phenotype complicating alemtuzumab treatment in T‐cell prolymphocytic leukemia

Johansson

Klein-Hitpaß

Röth

et al. 2020

European J of Haematology

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“…In addition, the inability of T-PLL cells to induce adequate responses to DNA insults was translated into therapeutic strategies to reactivate p53 via MDM2/MDMx inhibitors or targeting BCL2 family members (e.g. Venetoclax) (10,59,60). There are ongoing activities in the search for efficacious combinations of the, as single agent clinically only moderately active Venetoclax, with other classes of inhibitors in relapsed/ refractory (r/r) T-PLL (59)(60)(61)(62).…”

Section: Clinical Implications Derived From the Current Disease Modelmentioning

confidence: 99%

Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact

et al. 2021

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T-cell prolymphocytic leukemia (T-PLL) is the most common mature T-cell leukemia. It is a typically aggressively growing and chemotherapy-resistant malignancy with a poor prognosis. T-PLL cells resemble activated, post-thymic T-lymphocytes with memory-type effector functions. Constitutive transcriptional activation of genes of the T-cell leukemia 1 (TCL1) family based on genomic inversions/translocations is recognized as a key event in T-PLL’s pathogenesis. TCL1’s multiple effector pathways include the enhancement of T-cell receptor (TCR) signals. New molecular dependencies around responses to DNA damage, including repair and apoptosis regulation, as well as alterations of cytokine and non-TCR activation signaling were identified as perturbed hallmark pathways within the past years. We currently witness these vulnerabilities to be interrogated in first pre-clinical concepts and initial clinical testing in relapsed/refractory T-PLL patients. We summarize here the current knowledge on the molecular understanding of T-PLL’s pathobiology and critically assess the true translational progress around this to help appraisal by caregivers and patients. Overall, the contemporary concepts on T-PLL’s pathobiology are condensed in a comprehensive mechanistic disease model and promising interventional strategies derived from it are highlighted.

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The Combination of Venetoclax and Ibrutinib Is Effective in Relapsed/Refractory T‐prolymphocytic Leukemia and Influences Bcl‐2‐family Member Dependencies

Cited by 8 publications

References 0 publications

Advances and Perspectives in the Treatment of T-PLL

Advances and Perspectives in the Treatment of T-PLL

Mutations in PIGA cause a CD52‐/GPI‐anchor‐deficient phenotype complicating alemtuzumab treatment in T‐cell prolymphocytic leukemia

Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact

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