Activity and tolerability of the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim results of a phase Ib/II study.

Byrd, John C.; Blum, K. A.; Burger, Jan A.; Coutré, Steven; Sharman, Jeffrey P.; Furman, Richard R.; Flinn, Ian W.; Grant, Barbara; Richards, Donald A.; Zhao, Wanqi; Heerema, NA; Johnson, A. J.; Izumi, Raquel; Hamdy, Ahmed; O’Brien, Susan

doi:10.1200/jco.2011.29.15_suppl.6508

Cited by 38 publications

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“…The most striking clinical observation common to inhibitors of SYK, 20 BTK, 22 and PI3K␦ 19,21 is the rapid resolution of lymphadenopathy and splenomegaly within the first few weeks of therapy, which is accompanied by a transient increase in blood lymphocyte/CLL cell counts, suggesting CLL cell redistribution from the tissues into the PB. At least in the ibrutinib experience, the lymphocytosis appears to persist longer in previously treated CLL patients (n ϭ 27) where it can last for several months, 22,75 compared with previously untreated CLL patients (n ϭ 26). 75 …”

Section: Inhibitors Of Bcr-associated Kinases (Syk Btk Pi3k␦)mentioning

confidence: 99%

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Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling

Burger

Montserrat

2013

Blood

108

101

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Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3K␦ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCRsignaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy. (Blood. 2013;121(9):1501-1509) The microenvironment in CLLCirculating chronic lymphocytic leukemia (CLL) cells are nondividing resting B cells, but a significant fractions of tissue CLL cells proliferate in distinct microanatomical sites called proliferation centers or pseudofollicles, 1,2 accounting for a daily birth rate of 1%-2% of the entire CLL clone. 3 For survival and expansion, CLL cells rely on external signals from the microenvironment and normally undergo spontaneous apoptosis in tissue culture unless they are cocultured with stromal cells. 2 In the lymphatic tissues, CLL cells interact with various stromal cells, such as CD68 ϩ nurselike cells (NLC), 4-6 smooth muscle actin-positive mesenchymal stromal cells, 7 and CD4 ϩ T cells. 8,9 By inference from in vitro studies, we assume that stromal cells provide growth and survival signals to the CLL cells that are largely contact-dependent and can cooperate with intrinsic oncogenic lesions. 2,10,11 For example, interactions within the lymphatic tissue microenvironment result in BCR activation in the CLL cells, 11 and activation of this signaling cascade is favored by presence of unmutated IGHV genes and ZAP70 expression. 12 Although the affinity of CLL cells for stromal cells has long been recognized, the cross-talk between stroma and CLL cells only recently has been explored in a more systematic fashion. 11,13,14 We currently know that chemokine receptors and adhesion molecules are critical for the homing and retention of CLL cells in tissue compartments (bone marrow, secondary lymphatic tissues). 15 Gene expression profiling (GEP)...

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Section: Inhibitors Of Bcr-associated Kinases (Syk Btk Pi3k␦)mentioning

confidence: 99%

“…At least in the ibrutinib experience, the lymphocytosis appears to persist longer in previously treated CLL patients (n ϭ 27) where it can last for several months, 22,75 compared with previously untreated CLL patients (n ϭ 26). 75 …”

Section: Inhibitors Of Bcr-associated Kinases (Syk Btk Pi3k␦)mentioning

confidence: 99%

Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling

Burger

Montserrat

2013

Blood

108

101

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“…For patients who are candidates for SCT, the goal is often to achieve adequate cytoreduction followed by consolidation with reduced intensity allogeneic SCT (alloSCT). 63 ; n ϭ NR of 27*) 48 NR NR n ϭ 9; ORR 44%…”

Section: Treatment Options For Cit-refractory Cllmentioning

confidence: 99%

“…More mature results of the phase 1b/2 study were reported at the American Society of Clinical Oncology (ASCO) 2011 annual meeting. 63 Patients were enrolled in 2 cohorts: previously untreated over 65 years of age, or relapsed/refractory with at least 2 prior therapies. Thirty-nine patients of the 78 enrolled were evaluable for response.…”

Section: Bruton Tyrosine Kinase (Btk) Inhibitors: Pci-32765mentioning

confidence: 99%

The Treatment of Relapsed Refractory Chronic Lymphocytic Leukemia

Brown

2011

Hematology

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Despite the widespread use of highly effective chemoimmunotherapy (CIT), fludarabine-refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical problem associated with poor overall survival (OS). The traditional definition, which includes those patients with no response or relapse within 6 months of fludarabine, is evolving with the recognition that even patients with longer remissions of up to several years after CIT have poor subsequent treatment response and survival. Approved therapeutic options for these patients remain limited, and the goal of therapy for physically fit patients is often to achieve adequate cytoreduction to proceed to allogeneic stem cell transplantation (alloSCT). Fortunately, several novel targeted therapeutics in clinical trials hold promise of significant benefit for this patient population. This review discusses the activity of available and novel therapeutics in fludarabine-refractory or fludarabine-resistant CLL as well as recently updated data on alloSCT in CLL.

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“…It is not whether to consider a reduced-intensity allotransplant versus therapy-alternatives but in whom and when. New drugs for CLL are emerging rapidly including bendamustine, 10 Bruton-type kinase inhibitors, 11,12 adoptive immune-therapy with expanded, genetically-engineered autologous T-cells and chimeric anti-CD19 antibodies 13 and lenalidomide. 14 My colleague Michael Keating claims he will have CLL cured within three years (only because he is lazy [his comment]); let's give him five.…”

mentioning

confidence: 99%

Markov model of CLL transplants

Gale

2012

Bone Marrow Transplant

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Activity and tolerability of the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim results of a phase Ib/II study.

Cited by 38 publications

References 0 publications

Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling

Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling

The Treatment of Relapsed Refractory Chronic Lymphocytic Leukemia

Markov model of CLL transplants

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