Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response

Chanan‐Khan, Asher; Miller, Kena C.; Lawrence, David; Padmanabhan, Swaminathan; Miller, Austin; Hernandez-Illatazurri, Francisco; Czuczman, Myron S.; Wallace, Paul K.; Zeldis, Jerome B.; Lee, Kelvin

doi:10.1002/cncr.25748

Cited by 76 publications

(52 citation statements)

References 53 publications

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“…Furthermore, immunomodulatory drugs that seem to act to a large extent by down-regulating prosurvival factors such as VEGF, TNF, IL-8, and IL6, 46,48 may act in part by altering cytokine CL composition or relationships. The finding that tumor flare reaction that can occur with lenalidomide treatment predicts clinical response in CLL 49 suggests that modulation of inflammation contributes to the effectiveness of this drug; this is consistent with our finding that CLs of proinflammatory cytokines correlate with better outcome (CL2 and CL3).…”

supporting

confidence: 91%

Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia

Yan

Dozmorov

et al. 2011

Blood

103

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supporting

confidence: 91%

Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia

Yan

Dozmorov

et al. 2011

Blood

103

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“…78 Although inhibition of inflammatory cytokine secretion might improve its tolerability, the combination could also decrease the clinical benefit of lenalidomide, given evidence that its efficacy in CLL depends on the activation of an adaptive immune response. 79,80 The clinical success of such combinations may therefore depend on a more detailed understanding of differences between the various BCR inhibitors in regards to what pathways are inhibited and the resulting impact on cellular networks.…”

Section: Redefining Treatment Goals and The Development Of Rational Cmentioning

confidence: 99%

Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia

Wiestner

2012

Blood

150

128

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IntroductionOncogenic mutations in kinases have been identified in multiple cancers often leading to successful targeted therapy with kinase inhibitors. The paradigm in hematologic malignancies has been the discovery of the BCR-ABL fusion kinase in chronic myeloid leukemia and its successful targeting by tyrosine kinase inhibitors that changed the natural history of the disease. In contrast, possible disease-relevant mutations in kinases have been a rare finding in chronic lymphocytic leukemia (CLL). The most commonly mutated kinase in CLL is BRAF, with Ͻ 2% of patients affected. 1 However, kinase inhibitors that target signaling pathways that are essential for B-cell development, in particular, those targeting the B-cell receptor (BCR) have induced striking clinical responses. Here I briefly review these signaling pathways and discuss the ongoing clinical development of kinase inhibitors for the targeted therapy of CLL. Signaling pathways and their kinases in the pathogenesis of CLL Biology of CLLCLL is a malignancy of mature B cells involving blood, bone marrow, and lymphoid tissues. 2 CLL is the most common leukemia in Western countries and currently is most often diagnosed from an incidental blood count showing lymphocytosis. The median survival with early-stage disease is 10.7 years, but the clinical course is heterogeneous. 3 Two major CLL subtypes are distinguished by the presence or absence of somatic mutations in the immunoglobulin heavy chain variable region gene (IGHV), which encodes part of the antigen-binding domain of the BCR. Patients whose CLL cells express an unmutated IGHV gene (U-CLL) have a more rapidly progressive clinical course than patients whose CLL cells express a mutated IGHV gene (M-CLL). ZAP70, a nonreceptor tyrosine kinase essential for T-cell receptor signal transduction, is expressed in most cases of U-CLL and less frequently in M-CLL. ZAP70 expression correlates with more rapid disease progression in both subtypes defined by IGHV gene mutation status. 4The role of the microenvironment in CLL pathogenesis CLL cells in the blood are resting cells with a gene expression profile similar to memory B cells. 2 However, CLL cells in the lymph node and bone marrow show characteristics of activated B cells and demonstrate increased proliferation. 5 In the tissue sites, CLL proliferation is often highest in anatomic structures labeled as "proliferation centers" where CLL cells can interact with other cells, in particular T cells and stromal cells. 6 Thus, the biology of CLL cells in vivo depends on their anatomic location and is influenced by extrinsic signals from the tissue-microenvironment. In vitro, CLL cells undergo apoptosis unless appropriate microenvironmental factors are provided. This dependence of CLL cells on pathways that also promote normal B-cell development, expansion, and survival, [5][6][7][8][9] indicates that this tumor is "addicted to the host," constituting an example of a novel concept termed "non-oncogene addiction." 10 The term "microenvironment" collectively descri...

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“…Prophylaxis with low-dose oral prednisone (20 mg for 5 days followed by 10 mg for 5 days) decreased severity and delayed onset but did not reduce the incidence and may slow resolution (Chanan-Khan et al, 2011). Tumor flare reaction has also been reported mainly within the first cycle of lenalidomide in relapsed MCL patients, including 13/134 patients (10%, all grade 1/2) in the MCL-001 study and 4/26 patients (15%; 3 grade 2) reported by Eve and Rule (Eve & Rule, 2010;Goy et al, 2013).…”

Section: Tumor Flare Reactionmentioning

confidence: 94%

Approaches to Managing Safety With Lenalidomide in Hematologic Malignancies

Blumel¹,

Broadway-Duren²

2014

JADPRO

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Lenalidomide is an oral immunomodulatory agent approved in relapsed multiple myeloma with dexamethasone, for transfusion-dependent anemia in myelodysplastic syndrome associated with deletion 5q, and in relapsed/progressive mantle cell lymphoma following bortezomib. In recent clinical trials, lenalidomide has shown promising activity in hematologic malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Starting doses and dosing schedules vary by malignancy, with lenalidomide started at a lower dose for CLL than for NHL or multiple myeloma. Certain adverse events (AEs) are common across tumor types (e.g., neutropenia, thrombocytopenia, fatigue), whereas others are more often associated with CLL patients (e.g., tumor lysis syndrome and tumor flare reaction). Effective management requires awareness of these differences as well as appropriate prophylaxis, monitoring, and treatment of AEs. This article reviews the efficacy and safety of lenalidomide in CLL and NHL, focusing on approaches for the advanced practitioner to improve patient quality of life through optimal management of side effects. With these steps, lenalidomide can be administered safely, at the best starting doses and with minimal dose interruptions or reductions across hematologic malignancies.

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Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response

Cited by 76 publications

References 53 publications

Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia

Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia

Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia

Approaches to Managing Safety With Lenalidomide in Hematologic Malignancies

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