scholarly journals Treatment Approaches to Chronic Lymphocytic Leukemia With High-Risk Molecular Features

2021 ◽  
Vol 11 ◽  
Author(s):  
Lina van der Straten ◽  
Paul J. Hengeveld ◽  
Arnon P. Kater ◽  
Anton W. Langerak ◽  
Mark-David Levin
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Treatment Strategies ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Chromosome 11 ◽  
Comprehensive Overview ◽  
Treatment Approaches ◽  
Molecular Features

The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. Over the past decades, several cytogenetic, immunogenetic and molecular features have emerged that identify patients suffering from CLL with high-risk molecular features. These biomarkers can clearly aid prognostication, but may also be capable of predicting the efficacy of various treatment strategies in subgroups of patients. In this narrative review, we discuss treatment approaches to CLL with high-risk molecular features. Specifically, we review and provide a comprehensive overview of clinical trials evaluating the efficacy of chemotherapy, chemoimmunotherapy and novel agent-based treatments in CLL patients with TP53 aberrations, deletion of the long arm of chromosome 11, complex karyotype, unmutated IGHV, B cell receptor stereotypy, and mutations in NOTCH1 or BIRC3. Furthermore, we discuss future pharmaceutical and immunotherapeutic perspectives for CLL with high-risk molecular features, focusing on agents currently under investigation in clinical trials.

Understanding and Managing Ultra High-Risk Chronic Lymphocytic Leukemia

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 481-488 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Thorsten Zenz
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Poor Response ◽  
Lymphocytic Leukemia ◽  
Prognostic Models ◽  
Survival Times ◽  
Treatment Approaches ◽  
Ultra High Risk

AbstractModern treatment approaches such as chemoimmunotherapy (e.g., fludarabine/cyclophosphamide/rituximab or FCR) are highly effective in the majority of chronic lymphocytic leukemia (CLL) patients. However, there remains a small but challenging subgroup of patients who show ultra high-risk genetics (17p deletion, TP53 mutation) and/or poor response to chemoimmunotherapy. The median life expectancy of these patients is below 2 to 3 years with standard regimens. Accordingly, CLL with the 17p deletion (and likely also with sole TP53 mutation) should be treated with alternative strategies. While p53 defects appear to play a central role in our understanding of this ultra high-risk group, at least half of the cases will not be predictable based on existing prognostic models. Current treatment approaches for patients with p53 defects or poor response to chemoimmunotherapy should rely on agents acting independently of p53, such as alemtuzumab, lenalidomide, flavopiridol, and a growing number of novel compounds (or combinations thereof) currently available in clinical trials. Poor survival times of patients with ultra high-risk CLL suggest that eligible patients should be offered consolidation with reduced-intensity allogeneic stem-cell transplantation or experimental approaches in clinical trials.

scholarly journals Phosphoinositide 3-Kinase Signaling in the Tumor Microenvironment: What Do We Need to Consider When Treating Chronic Lymphocytic Leukemia With PI3K Inhibitors?

2021 ◽  
Vol 11 ◽  
Author(s):  
Ebru Aydin ◽  
Sebastian Faehling ◽  
Mariam Saleh ◽  
Laura Llaó Cid ◽  
Martina Seiffert ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Treatment Strategies ◽  
Cell Receptor ◽  
Pi3k Pathway ◽  
Lymphocytic Leukemia ◽  
Pi3k Signaling ◽  
Extracellular Signals ◽  
Pi3k Inhibition

Phosphoinositide 3-kinases (PI3Ks) and their downstream proteins constitute a signaling pathway that is involved in both normal cell growth and malignant transformation of cells. Under physiological conditions, PI3K signaling regulates various cellular functions such as apoptosis, survival, proliferation, and growth, depending on the extracellular signals. A deterioration of these extracellular signals caused by mutational damage in oncogenes or growth factor receptors may result in hyperactivation of this signaling cascade, which is recognized as a hallmark of cancer. Although higher activation of PI3K pathway is common in many types of cancer, it has been therapeutically targeted for the first time in chronic lymphocytic leukemia (CLL), demonstrating its significance in B-cell receptor (BCR) signaling and malignant B-cell expansion. The biological activity of the PI3K pathway is not only limited to cancer cells but is also crucial for many components of the tumor microenvironment, as PI3K signaling regulates cytokine responses, and ensures the development and function of immune cells. Therefore, the success or failure of the PI3K inhibition is strongly related to microenvironmental stimuli. In this review, we outline the impacts of PI3K inhibition on the tumor microenvironment with a specific focus on CLL. Acknowledging the effects of PI3K inhibitor-based therapies on the tumor microenvironment in CLL can serve as a rationale for improved drug development, explain treatment-associated adverse events, and suggest novel combinatory treatment strategies in CLL.

scholarly journals Managing Patients With TP53-Deficient Chronic Lymphocytic Leukemia

2017 ◽  
Vol 13 (6) ◽  
pp. 371-377 ◽  
Author(s):  
Jennifer Edelmann ◽  
John G. Gribben
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Clinical Trial Data ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Chromosome 17

Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression. Compounds now approved for the treatment of TP53-deficient CLL are the two B-cell receptor inhibitors ibrutinib and idelalisib and the BH3 mimetic venetoclax. All three compounds were approved on the basis of favorable response rates that, importantly, revealed no differences between TP53-competent and TP53-deficient CLL cases. Using these compounds, longer-lasting remissions in patients with TP53-deficient CLL could be demonstrated for the first time. Whether TP53 alterations will maintain their significance as adverse prognostic factors in treatment strategies involving novel compounds needs to be assessed. This review provides an overview of current treatment options for 17p-deleted/ TP53-mutated CLL, including those compounds that are already approved by the US Food and Drug Administration or are under advanced clinical investigation. Available clinical trial data are discussed, as is the use of novel targeted treatment options in the context of transplant strategies, and an algorithm for off-study treatment of 17p-deficient CLL is suggested.

scholarly journals Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

2017 ◽  
Vol 1 (21) ◽  
pp. 1867-1875 ◽  
Author(s):  
Kamira Maharaj ◽  
Eva Sahakian ◽  
Javier Pinilla-Ibarz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Treatment Strategies ◽  
Drug Efficacy ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Bcr Signaling ◽  
Signaling Inhibitors

Abstract Approved therapies that target the B-cell receptor (BCR) signaling pathway, such as ibrutinib and idelalisib, are known to show activity in chronic lymphocytic leukemia (CLL) via their direct effects on crucial survival pathways in malignant B cells. However, these therapies also have effects on T cells in CLL by mediating toxicity and possibly controlling disease. By focusing on the effects of BCR signaling inhibitors on the T-cell compartment, we may gain new insights into the comprehensive biological outcomes of systemic treatment to further understand mechanisms of drug efficacy, predict the toxicity or adverse events, and identify novel combinatorial therapies. Here, we review T-cell abnormalities in preclinical models and patient samples, finding that CLL T cells orchestrate immune dysfunction and immune-related complications. We then continue to address the effects of clinically available small molecule BCR signaling inhibitors on the immune cells, especially T cells, in the context of concomitant immune-mediated adverse events and implications for future treatment strategies. Our review suggests potentially novel mechanisms of action related to BCR inhibitors, providing a rationale to extend their use to other cancers and autoimmune disorders.

scholarly journals The Difficult-to-Treat del 17 p Patient—A Case Report in Chronic Lymphocytic Leukemia

Medicina ◽  
2021 ◽  
Vol 58 (1) ◽  
pp. 33
Author(s):  
Ana-Maria Moldovianu ◽  
Ana Manuela Crisan ◽  
Zsofia Varady ◽  
Daniel Coriu
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Risk Patients ◽  
Potential Benefits

Chronic lymphocytic leukemia (CLL) treatment strategies have evolved to include mechanism-driven drugs but now raise new questions regarding their optimum timing and sequencing. In high-risk patients, switching from pathway inhibitors to allogeneic stem cell transplantation (allo-HCT) is still a matter of intense debate. We report the case of a CLL patient with 17 p deletion treated with ibrutinib as a bridge to allo-HCT. Early relapse after allo-HCT urged the initiation of salvage therapy, including donor lymphocytes infusions, ibrutinib, and venetoclax. We aim to outline and discuss the potential benefits of novel therapies, the current role of allo-HCT in CLL, drug timing and sequencing, and the unmet need to improve the long-term outcome of high-risk CLL patients.

scholarly journals Bruton tyrosine kinase inhibitors for the frontline treatment of chronic lymphocytic leukemia

2020 ◽  
Vol 27 (6) ◽  
Author(s):  
V. Banerji ◽  
A. Aw ◽  
S. Robinson ◽  
S. Doucette ◽  
A. Christofides ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Variable Region ◽  
Tp53 Gene ◽  
Cell Receptor ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Btk Inhibitors

Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed adult leukemia in Canada. Biologic heterogeneity of CLL can be observed between patients which results in variable disease trajectory and response to therapy. Notably, patients with high-risk features such as the presence of deletions in chromosome 17p, aberrations in the TP53 gene, or unmutated immunoglobulin heavy chain variable region genes have inferior outcomes and response to standard chemoimmunotherapy compared to patients without these features. Novel agents which target the B cell receptor signalling pathway, such as Bruton’s tyrosine kinase (BTK) inhibitors have demonstrated clinical efficacy and safety in patients with treatment-naïve CLL, particularly in those with high-risk features. However, due to the current lack of head-to-head trials comparing BTK inhibitors, selection of the optimal BTK inhibitor for patients with CLL is unclear and requires the consideration of multiple factors. This review focuses on the efficacy, safety, and pharmacological features of the BTK inhibitors that are approved or are under clinical development and discusses the practical considerations for the use of these agents in the Canadian treatment landscape.

Tailored Treatment Strategies for Chronic Lymphocytic Leukemia in a Rapidly Changing Era

2019 ◽  
pp. 487-498
Author(s):  
Danielle Brander ◽  
Prioty Islam ◽  
Jacqueline C. Barrientos
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Disease Assessment ◽  
Clinical Endpoints ◽  
Tailored Treatment ◽  
Signaling Inhibitors

The treatment landscape for chronic lymphocytic leukemia (CLL) is rapidly evolving, with multiple agents recently approved. They include a glycoengineered monoclonal antibody (obinutuzumab), B-cell receptor signaling inhibitors (ibrutinib, idelalisib, and duvelisib), and the BCL-2 inhibitor (venetoclax). These compounds are dramatically changing the natural course of the disease. Nonetheless, despite improved survival rates, particularly in higher-risk disease (older adults, patients with unmutated IGHV, del(11q), and del(17p)/ TP53 mutated), there is still room for progress. Given the panoply of highly effective therapies commercially available, it is important to define a tailored treatment strategy for this heterogeneous condition that considers balance of treatment efficacy versus toxicity or tolerance. This article summarizes the most promising clinical advances by reviewing the data from recent clinical trials and discussing meaningful clinical endpoints, including the role of minimal residual disease assessment. The recent development of therapies targeting dysregulated pathways is revolutionary and may ultimately lead us to not only achieve prolonged remission durations but also envision the possibility of a functional cure for a larger population of patients.

scholarly journals Clinical Impact of Stereotyped Antigen Receptors in Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3280-3280
Author(s):  
Panagiotis Baliakas ◽  
Anastasia Hadzidimitriou ◽  
Lesley-Ann Sutton ◽  
Evangelia Minga ◽  
Andreas Agathangelidis ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clonal Evolution ◽  
Molecular Classification ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Molecular Diagnostic ◽  
Median Percentage ◽  
Molecular Features ◽  
Mutational Status ◽  
Ighv Gene

Abstract In chronic lymphocytic leukemia (CLL), the molecular features of the clonotypic B-cell receptor immunoglobulins (BcR IG) are set from the birth of the clone and in contrast to genetic aberrations, remain stable overtime, rendering the BcR IG a reference biomarker that is usually not significantly affected by clonal evolution. Approximately 30% of CLL cases carry quasi-identical BcR IGs and can be assigned to distinct stereotyped subsets. While preliminary evidence alludes to BcR IG stereotypy being relevant from a clinical viewpoint, this aspect has never been explored systematically or in a cohort of adequate size to enable meaningful conclusions. In order to assess the clinical implications of BcR IG stereotypy, we evaluated clinicobiological data from 8593 CLL patients, particularly focusing on 14 major stereotyped subsets of cases with unmutated (U-CLL) or mutated IGHV genes (M-CLL). The largest subset was #2 (n=254, 3%), within which 156 and 98 cases were M-CLL and U-CLL, respectively, followed by U-CLL subsets #1 (n=173, 2%) and #7 (n=123, 1.4%). Amongst M-CLL, the largest subsets were #4 (n=94, 1.1%) and #148 (n=92, 1%). Stereotyped subsets, even of the same mutational category i.e. U-CLL or M-CLL, exhibited significant clinicobiological differences regarding: age at diagnosis (median age ranging from 53-68 years, p<0.001); gender distribution (male/female ratios ranging from 0.85-4.4, p<0.001); the frequency of advanced stage disease (Binet C) at diagnosis (ranging from 9-21%, p<0.001); CD38 positivity (median percentage of positive cells ranging from 2-73%, p<0.05). Moving to cytogenetic findings, we detected subset-biased spectra of FISH-detected aberrations which can be summarized as follows: (i) isolated del(13q) varied from 10% in subset #8 (U-CLL), to 29% in subsets #59 (U-CLL) and #16 (M-CLL), and >75% in M-CLL subsets #77 and #148 (p<0.001); (ii) trisomy 12 was absent in subsets #31 (U-CLL) and #77 (M-CLL), in 20% of subset #201 (M-CLL) and, 60% in subset #8 (U-CLL) (p<0.001); (iii) del(11q) ranged from 69% in subset #31 (U-CLL) to 12% in subset #8 (U-CLL) and 0% in M-CLL subsets #16 and #201 (p<0.001); (iv) del(17p): absent from all M-CLL subsets except #148 (7.5%); absent from U-CLL subsets #5 and #59, and present in 19% and 17% of stereotyped subset #8 and #6 cases, respectively (p<0.05). We considered subset #2 separately since it included both M-CLL and U-CLL and identified a distinctive clinicobiological profile characterized by a constellation of features, including high incidence of Binet stage C disease (21%), CD38 positivity (41%) and certain cytogenetic abnormalities i.e. del(13q) (56%) and del(11q) (23%) and, in contrast, low frequency of del(17p) (4.5%). Notably, no differences were found between U-CLL versus M-CLL subset #2 cases regarding the incidence of these parameters. Survival analysis for time-to-first-treatment (TTFT) revealed that each stereotyped subset exhibited a distinct clinical course, different from that of other subsets even with similar IGHV gene mutational status and/or expressing the same IGHV gene. Interestingly, subsets #1 and #2 demonstrated a similar TTFT to that of del(17p) positive cases, while within subset #2 the clinical outcome was independent of IGHV mutational status. By integrating BcR IG stereotypy into the Döhner cytogenetic prognostication model, we found that subsets #1, #2 and #4, collectively accounting for ~7% of our series, and representing both U-CLL and M-CLL, constituted distinct clinical entities, with the latter exhibiting a particularly indolent disease even when compared to isolated del(13q) cases or cases with no cytogenetic aberrations. Finally, in multivariate analysis for TTFT, assignment to subset #2 emerged as a new independent unfavorable factor (p=0.002); furthermore, when restricting the analysis to Binet A cases, subset #2 exhibited the second highest hazard ratio after U-CLL. In conclusion, the molecular classification of CLL based on BcR IG stereotypy refines prognostication beyond IG mutational status and improves the Döhner hierarchical model. Hence, we suggest that a compartmentalized approach focusing on and comparing different subsets sheds light on CLL clinical behavior and biology and that BcR IG stereotypy represents a companion molecular diagnostic for personalized medicine in CLL. Disclosures Montillo: Janssen: Honoraria.

Combined Inhibition of mTOR and DNA-PK Blocks Survival, Adhesion, Proliferation and Chemoresistance in Primary Chronic Lymphocytic Leukemia (CLL) Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1981-1981 ◽  
Author(s):  
Rachel Thijssen ◽  
Gregor van Bochove ◽  
Ingrid AM Derks ◽  
Johanna ter Burg ◽  
Martin FM de Rooij ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Dna Repair ◽  
Lymph Node ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia

Abstract CLL progression and chemoresistance can result from signals from the lymph node (LN) microenvironment and from acquired aberrations in the DNA damage repair (DDR) pathway. Clinical targeting of kinases upstream in the B cell receptor (BCR) activation pathway, such as Btk or PI3Kδ results in egress of cells from the LN microenvironment [1,2]. Such prolonged lymphocytosis during kinase-inhibitor treatment appears to pose no clinical disadvantage [3]. However, it enhances the chance of accumulating resistance-inducing mutations, and therefore drugs that combine LN egress with direct cytoxicity could provide an improved therapeutic strategy for CLL. The mTOR complex, consisting of mTOR1 and 2, is the main downstream kinase of the PI3K/Akt pathway and contributes to proliferation and survival. DNA-PK is a kinase required for non-homologous end joining (NHEJ) of the DNA repair pathway. Inhibitors of crucial components of the DDR pathway might be active in CLL, especially in patients harboring mutations in DNA repair molecules such as Ataxia telangiectasia mutated (ATM). In this study the potency of a novel dual mTOR1,2 and DNA-PK inhibitor (CC-115) was studied in primary CLL samples of different prognostic subgroups with respect to induction of cytotoxicity, and inhibition of adhesion, CD40-mediated chemoresistance and proliferation. In vitro, CC-115 inhibited mTOR1 and 2 and also affected the DDR reflected by inhibition of irradiation-induced γH2AX, not only in ATM-mutated but also in ATM-wild type CLL cells. CC-115 showed induction of caspase-dependent cell killing (IC50=0.625µM) which was more robust than selective kinase inhibitors (table 1), irrespective of p53 or ATM status. This cytotoxic effect was not observed in the T cells from CLL patients. BCR-mediated adhesion to fibronectin [4] was inhibited by CC-115 to a similar extent as PI3Kδ inhibitor (idelalisib) (table 1). CD40-mediated chemoresistance [5] could be reverted completely by CC-115 while more specific inhibitors had only modest effects. CLL proliferation induced by CD40L+IL-21 treatment [6] was completely blocked by both CC-115 and a dual mTOR1,2 inhibitor but not by inhibitor of the more upstream kinase PI3Kδ (table 1). In conclusion, these data show that CC-115 induces direct cytotoxicity and inhibits several clinically relevant biological features of CLL, and provide a rationale for clinical trials with CC-115 in CLL patients. [1] Hoellenriegel J, Meadows SA, Sivina M et al. The phospoinositide 3’-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011;(118):3603-3612 [2] Burger JA. Bruton’s Tyrosine Kinase (BTK) Inhibitors in Clinical Trials. Curr Hematol Malig Rep (2014) 9:44–49 [3] Herman SE, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014 Apr 4. doi: 10.1038/leu.2014.122. [Epub ahead of print] [4] de Rooij MF, Kuil A, Geest CR et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012;(119):2590-2594. [5] Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocitic leukemia cells correlates with survival capacity. Blood 2007;(109):1660-1668. [6] Pascutti MF, Jak M, Tromp JM et al. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood 2013;(122):3010-3019.Smit LA, Hallaert DY, Spijker R et al. Table 1. The effect of the mTOR1,2 + DNA-PK inhibitor (CC-115), mTOR1,2 inhibitor (CC-214), DNA-PK inhibitor (NU7441) and PI3Kδ inhibitor (idelalisib) on CLL cells in functional assays. CC-115 CC-214 NU7441 Idelalisib (CAL-101) Target mTOR1,2 DNA-PK mTOR1,2 DNA-PK PI3Kδ Cytotoxicity (IC50) 0.625 µ M >10µM >10µM >10µM Inhibition of adhesion 40%** 0% 22% 48%** Activation Inhibition of CD40-mediated resistance to fludarabine (6.25 µ M) 92%** 42%* n.d. 21% Inhibition of CD40L+IL21 induced proliferation 98%** 98%* 28% 51%** n.d. = not done The one sample T test was used to determine the significance of differences between means of treated samples and normalized values of untreated samples (100%). * p <0,05;** p<0,01 Disclosures Kersten: Celgene: Research Funding. Kater:Celgene: Research Funding.

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