Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope

Goede, Valentin; Hallek, Michael

doi:10.1007/s40266-015-0308-3

Cited by 5 publications

(3 citation statements)

References 54 publications

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“…Similar to other cancers, inherent and/or acquired resistance to therapeutic antibodies is common in CLL, and in the relapsed setting, is a significant challenge in treating CLL patients [84,85]. Recently, we and others have made significant progress in understanding the molecular mechanisms that drive resistance to therapeutic antibodies in CLL.…”

Section: Macrophage-mediated Therapeutic Antibody Resistance In Cllmentioning

confidence: 99%

The duality of macrophage function in chronic lymphocytic leukaemia

Chen

Mapp

Blumenthal

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia and, in some patients, is accompanied by resistance to both chemotherapeutics and immunotherapeutics. In this review we will discuss the role of tumour associated macrophages (TAMs) in promoting CLL cell survival and resistance to immunotherapeutics. In addition, we will discuss mechanisms by which TAMs suppress T-cell mediated antitumour responses. Thus, targeting macrophages could be used to i) reduce the leukaemic burden via the induction of T-cell-mediated antitumour responses, ii) to reduce pro-survival signalling and enhance response to conventional chemotherapeutics or iii) enhance the response to therapeutic antibodies in current clinical use.

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Section: Macrophage-mediated Therapeutic Antibody Resistance In Cllmentioning

confidence: 99%

The duality of macrophage function in chronic lymphocytic leukaemia

Chen

Mapp

Blumenthal

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…Therapeutic antibodies targeting CD20, such as obinutuzumab and rituximab, are used in firstand second-line treatments for CLL (8)(9)(10)(11)(12). Although of proven clinical value in CLL treatment, acquired resistance to antibody therapies remains a serious issue and contributes to relapse and treatment failure (13).…”

Section: Introductionmentioning

confidence: 99%

SIRPα Suppresses Response to Therapeutic Antibodies by Nurse Like Cells From Chronic Lymphocytic Leukemia Patients

et al. 2021

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Targeted antibody therapies improve outcomes for chronic lymphocytic leukemia (CLL) patients. However, resistance often develops. We have previously shown that resistance to therapeutic antibodies, by monocyte derived macrophages (referred to as nurse like cells, NLCs), from CLL patients is characterized by suppression of antibody dependent phagocytosis (ADP). The mechanism(s) contributing to the muted ADP responses remain unresolved. In this regard, an innate immune checkpoint was recently described that uses the CD47:SIRPα axis to suppress phagocytic responses by macrophages. In this study we examine whether the SIRPα axis regulates ADP responses to the anti-CD20 antibody, obinutuzumab, by NLCs. Using siRNA depletion strategies we show that SIRPα is a suppressor of ADP responses. Moreover, we show that this innate immune checkpoint contributes to the resistance phenotype in NLCs derived from CLL patients. Finally, we show that SIRPα suppression is mediated via the phosphatase, Shp1, which in turn suppresses SYK-dependent activation of ADP. Thus, we identify a druggable pathway that could be exploited to enhance sensitivity to existing therapeutic antibodies used in CLL. This is the first study to show that activation of the CD47:SIRPα innate immune checkpoint contributes to ADP resistance in NLCs from CLL patients.

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“…This has shown an overall response rate (ORR) of greater than 95% and complete remission of 72% for patients without the high risk 17p deletion. 6 , 7 However, this treatment is not an option for elderly patients or those with significant comorbidities. Although bendamustine with rituximab (BR) is a less-toxic alternative with equivalent progression-free survival (PFS) for patients 65 years or older, neither FCR nor BR are attractive options in the relapsed setting in this population due to cumulative toxicities.…”

Section: Introductionmentioning

confidence: 99%

Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas

Madanat

Smith

Hill

2016

BLCTT

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Chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma are indolent B-cell lymphoproliferative disorders that mainly affect an older population. Although the majority of patients in need of treatment derive significant benefit from conventional chemotherapeutic agents as well as monoclonal antibodies, less toxic and more effective treatments are needed. Novel agents that inhibit the B-cell receptor signaling pathway have shown promising outcomes in these disorders. Idelalisib is a potent selective oral inhibitor of phosphatidylinositol 3-kinase delta and has shown significant clinical activity in B-cell malignancies. In this review, we summarize the clinical trial data using idelalisib as monotherapy or in combination with rituximab for the treatment of relapsed/refractory disease. The adverse effect profile includes autoimmune disorders such as transaminitis, colitis, and pneumonitis. Given the efficacy and manageable toxicity profile of idelalisib, it is being increasingly incorporated into the management of indolent B-cell malignancies.

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Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope

Cited by 5 publications

References 54 publications

The duality of macrophage function in chronic lymphocytic leukaemia

The duality of macrophage function in chronic lymphocytic leukaemia

SIRPα Suppresses Response to Therapeutic Antibodies by Nurse Like Cells From Chronic Lymphocytic Leukemia Patients

Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas

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