Establish the safety and the maximum tolerated dose (MTD) of orally administered PCI-32765 in patients with recurrent B cell lymphoma. Determine pharmacokinetics (PK) of orally administered PCI-32765 Measure pharmacodynamic parameters to include drug occupancy of Btk, the target enzyme, and effect on biological markers of B cell function Samples for pharmacokinetics and pharmacodynamics will be collected as outlined in the protocol and shipped to Pharmacyclics, Inc. as specified below. We performed a trial to assess inhibition of upstream BCR signaling. Based on work from Lou Staudt showing that inhibition of Bruton's Tyrosine Kinase (BTK), is lethal in ABC but not GCB cell lines, we hypothesized that ibrutinib, a covalent inhibitor of BTK, would be clinically active in ABC but not GCB DLBCL. To assess this hypothesis, we performed a phase I/II study of ibrutinib 560 mg/day orally until disease progression in 70 subjects with relapsed or refractory de novo DLBCL. Overall, responses were observed in 25% (20/80) of subjects, including partial responses (PR; n = 12) and complete responses (CR; n = 8). With a median post-treatment follow-up period of 11.53 months, median progression-free survival (PFS) and overall survival (OS) were 1.64 months and 6.41 months, respectively. When analyzed by GEP cell of origin, 37% (14/38) of patients with ABC responded compared to 5% of GCB DLBCL, confirming our hypothesis. We sequenced the ABC tumors to help understand the relationship between mutations and ibrutinib response. Gain-of-function mutations in the BCR subunit CD79b occurred in 23% of ABC biopsies with 55.5% (5/9) responding to ibrutinib. Notably, 31% (9/29) of tumors with wild-type CD79B also responded, suggesting that a BCR mutation is not required for addiction to BCR signaling. The TLR signaling pathway also contributes to NF-kB activation through MYD88, which contained activating mutations in 39% of tumor biopsies, and could diminish the effect of ibrutinib through alternative activation NF-kB. Alternatively, because MYD88 and CD79B mutations co-occur more often than expected by chance, there may be cooperation between these pathways. In this regard, response rates to ibrutinib were similar in tumors with (4/12; 33.3%) and without (10/25; 40%) MYD88 mutations, whereas tumors with MYD88 mutation alone was unresponsive (0/7). Similar results were found in ABC cell lines-left panel above. This suggests two pathogenic mechanisms-one involves MYD88/CD79B cooperation in BCR signaling, and one due to oncogenic TLR signaling independent of BCR signaling. Expectedly, tumor with CADR11 activing mutations were unresponsive to ibrutinib. Based on these showing ibrutinib activity in ABC DLBCL, we worked with Janssen as lead PI's to design and execute a phase III randomized study of R-CHOP with and without ibrutinib in patients with untreated de novo ABC (non-GCB) DLBCL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011354-09
Application #
9779873
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Dunleavy, Kieron; Roschewski, Mark; Wilson, Wyndham H (2012) Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep 7:208-15
Roschewski, Mark; Wilson, Wyndham H (2012) EBV-associated lymphomas in adults. Best Pract Res Clin Haematol 25:75-89
Eberle, Franziska C; Song, Joo Y; Xi, Liqiang et al. (2012) Nodal involvement by cutaneous CD30-positive T-cell lymphoma mimicking classical Hodgkin lymphoma. Am J Surg Pathol 36:716-25
Dunleavy, Kieron; Grant, Cliona; Eberle, Franziska C et al. (2012) Gray zone lymphoma: better treated like hodgkin lymphoma or mediastinal large B-cell lymphoma? Curr Hematol Malig Rep 7:241-7
Dunleavy, Kieron; Wilson, Wyndham H (2012) How I treat HIV-associated lymphoma. Blood 119:3245-55
Degheidy, Heba A; Venzon, David J; Farooqui, Mohammed Z H et al. (2012) Combined normal donor and CLL: Single tube ZAP-70 analysis. Cytometry B Clin Cytom 82:67-77
Wilson, Wyndham H; Jung, Sin-Ho; Porcu, Pierluigi et al. (2012) A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica 97:758-65
Royo, C; Navarro, A; Clot, G et al. (2012) Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease. Leukemia 26:1895-8
Herishanu, Yair; Perez-Galan, Patricia; Liu, Delong et al. (2011) The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117:563-74
Mansoor, Adnan; Pittaluga, Stefania; Beck, Paul L et al. (2011) NK-cell enteropathy: a benign NK-cell lymphoproliferative disease mimicking intestinal lymphoma: clinicopathologic features and follow-up in a unique case series. Blood 117:1447-52

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