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 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 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.

How I treat chronic lymphocytic leukemia after venetoclax

Blood ◽  
2021 ◽  
Author(s):  
Thomas E Lew ◽  
Constantine S. Tam ◽  
John F. Seymour
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Treatment Options ◽  
Cell Receptor ◽  
Resistance Mechanisms ◽  
Lymphocytic Leukemia ◽  
Bcl2 Family ◽  
Clinical Scenarios ◽  
Car T

Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease (uMRD) and facilitating time-limited treatment without utilizing chemotherapy. Although response rates are high and durable disease control is common, longer-term follow-up of patients with relapsed and refractory (RR) disease, especially in the presence of TP53 aberrations, demonstrates frequent disease resistance and progression. Although the understanding of venetoclax resistance remains incomplete, progressive disease (PD) is typified by oligoclonal leukemic populations with distinct resistance mechanisms, including BCL2 mutations, upregulation of alternative BCL2 family proteins and genomic instability. Although most commonly observed in heavily pre-treated patients with disease refractory to fludarabine and harboring complex karyotype (CK), Richter transformation (RT) presents a distinct and challenging manifestation of venetoclax resistance. For patients with progressive CLL after venetoclax, treatment options include B-cell receptor pathway inhibitors (BCRis), allogeneic stem cell transplantation (SCT), chimeric antigen receptor (CAR) T-cells, and venetoclax re-treatment for those with disease relapsing after time-limited therapy. However, data to inform clinical decisions for these patients are limited. We review the biology of venetoclax resistance and outline an approach to the common clinical scenarios encountered after venetoclax-based therapy that will increasingly confront practising clinicians.

Allotransplantation for chronic lymphocytic leukemia

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 602-609 ◽  
Author(s):  
Peter Dreger
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Immune Modulation ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Lymphocytic Leukemia ◽  
Successful Outcome ◽  
Mortality And Morbidity ◽  
Poor Risk ◽  
Leukemic Clone

AbstractEfforts to develop curative treatment strategies for chronic lymphocytic leukemia (CLL) in recent years have focused on allogeneic stem cell transplantation (alloSCT). The crucial anti-leukemic principle of alloSCT in CLL appears to be the immune-mediated anti-host activities conferred with the graft (graft-versus-leukemia effects, GVL). Evidence for GVL in CLL is provided by studies analyzing the kinetics of minimal residual disease on response to immune modulation after transplantation, suggesting that GVL can result in complete and durable suppression of the leukemic clone. AlloSCT from matched related or unrelated donors can overcome the treatment resistance of poor-risk CLL, ie, purine analogue refractory disease and CLL with del 17p-. Even with reduced-intensity conditioning, alloSCT in CLL is associated with significant mortality and morbidity due to graft-versus-host disease, which has to be weighed against the risk of the disease when defining the indication for transplantation. Therefore, it can be regarded as a reasonable treatment option only for eligible patients who fulfill accepted criteria for poor-risk disease. If alloSCT is considered, it should be performed before CLL has advanced to a status of complete refractoriness to assure an optimum chance for a successful outcome. Prospective trials are underway to prove whether allo-SCT can indeed change the natural history of poor-risk 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.

Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia

2017 ◽  
Vol 58 (12) ◽  
pp. 2777-2785 ◽  
Author(s):  
Carolyn Owen ◽  
Anna Christofides ◽  
Nathalie Johnson ◽  
Tatiana Lawrence ◽  
David MacDonald ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Disease Assessment ◽  
Minimal Residual

scholarly journals Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 535-537 ◽  
Author(s):  
Farrukh T. Awan ◽  
Neil E. Kay ◽  
Melanie E. Davis ◽  
Wenting Wu ◽  
Susan M. Geyer ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Myeloid Cell ◽  
Progression Free Survival ◽  
Poor Response ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Phase 2 Study ◽  
Significant Difference

Abstract Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. Increased Mcl-1 expression is associated with failure to achieve remission after treatment with fludarabine and chlorambucil in patients with chronic lymphocytic leukemia (CLL). However, the influence of Mcl-1 expression has not been examined in CLL trials using chemoimmunotherapy. We investigated Mcl-1 protein expression prospectively as part of a phase 2 study evaluating the efficacy of pentostatin, cyclophosphamide, and rituximab in patients with untreated CLL. No significant difference by Mcl-1 expression was noted in pretreatment or response parameters. However, in patients with higher Mcl-1 expression, both minimal residual disease-negative status and progression-free survival was found to be significantly reduced (57% vs 19%, P = .01; 50.8 vs 18.7 months; P = .02; respectively). Mcl-1 expression may therefore be useful in predicting poor response to chemoimmunotherapy. These findings further support pursuing treatment strategies targeting this important antiapoptotic protein. (Because the trials described were conducted before the requirement to register them was implemented, they are not registered in a clinical trial database.)

scholarly journals Updates from the 2017 American Society of Hematology annual meeting: practice-changing studies in untreated chronic lymphocytic leukemia

2018 ◽  
Vol 25 (1) ◽  
pp. 91
Author(s):  
C. Owen ◽  
C. Toze ◽  
A. Christofides
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Annual Meeting ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Meeting Report ◽  
Phase Ii Studies ◽  
Novel Treatment Strategies ◽  
American Society

The 2017 annual meeting of the American Society of Hematology took place 9–12 December in Atlanta, Georgia. At the meeting, the oral presentations included results from key studies on the first-line treatment of chronic lymphocytic leukemia. A series of phase ii studies focusing on the efficacy and safety of novel treatment strategies were especially notable. One concerned the health-related quality of life results from the gibb study, which had examined the combination of obinutuzumab and bendamustine. A second evaluated the venetoclax–ibrutinib regimen in patients with high-risk disease. The third assessed the combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab in patients with mutated immunoglobulin heavy-chain variable region genes. The fourth examined the combination of ibrutinib, fludarabine, cyclophosphamide, and rituximab in younger patients. And the final study evaluated obinutuzumab–ibrutinib followed by a minimal residual disease strategy in fit patients. Our meeting report describes the foregoing studies and presents interviews with investigators and commentaries by Canadian hematologists about the potential effects on Canadian practice.

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