Ibrutinib (Imbruvica): The First-in-Class Btk Inhibitor for Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia

Ibrutinib is a major new addition to the therapeutic armamentarium for chronic lymphocytic leukemia, mantle cell lymphoma, Waldenstrom’s macroglobulinemia, and chronic graft versus host disease. Though ibrutinib has proven to be a revolutionary new small molecule agent, and has relatively minimal toxicity as compared to traditional chemotherapy, infections have emerged as a major complication of therapy. While fungal infections have been the most problematic (including CNS aspergillosis), zoster, hepatitis B reactivation, and chronic hepatitis E have been reported in association with ibrutinib therapy. This report describes a case of herpes encephalitis in an 86-year-old Waldenstrom’s patient receiving ibrutinib and speculates as to whether this late life encephalitis may have been related to ibrutinib.

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Multicenter Phase II Study of Fludarabine Phosphate for Patients With Newly Diagnosed Lymphoplasmacytoid Lymphoma, Waldenström's Macroglobulinemia, and Mantle-Cell Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.2.546 ◽

1999 ◽

Vol 17 (2) ◽

pp. 546-546 ◽

Cited By ~ 132

Author(s):

James M. Foran ◽

Ama Z.S. Rohatiner ◽

Bertr Coiffier ◽

Tiziano Barbui ◽

Stephen A. Johnson ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Newly Diagnosed ◽

Waldenström’S Macroglobulinemia ◽

Fludarabine Phosphate ◽

Mantle Cell ◽

Duration Of Response ◽

Waldenstrom's Macroglobulinemia ◽

Waldenström's Macroglobulinemia

PURPOSE: Fludarabine phosphate (F-AMP) has significant activity in follicular lymphoma and in B-cell chronic lymphatic leukemia, where it has demonstrated high complete response (CR) rates. Lymphoplasmacytoid (LPC) lymphoma, Waldenström's macroglobulinemia (WM), and mantle-cell lymphoma (MCL) also present with advanced-stage disease and are incurable with standard alkylator-based chemotherapy. A phase II trial was undertaken to determine the activity of F-AMP in patients newly diagnosed with these diseases. PATIENTS AND METHODS: Between 1992 and 1996, 78 patients (aged 18 to 75 years) received intravenous F-AMP (25 mg/m2/d for 5 days, every 4 weeks) until maximum response, plus two further cycles as consolidation. The primary end point was response rate; secondary end points included time to progression (TTP), duration of response, and overall survival (OS). RESULTS: Forty-four (62%) of 71 assessable patients had a response to F-AMP (LPC lymphoma, 63%; WM, 79%; MCL, 41%); the CR rate was 15%. At a median follow-up of 1.5 years, 19 of 44 responding patients have had progression of lymphoma; the median duration of response was 2.5 years. The median survival has not yet been reached. There was no significant difference in the duration of response or OS between patients with different histologies; TTP was shorter in patients with MCL (P = .015). Myelosuppression was relatively common, and the treatment-related mortality (TRM) was 5%, mostly associated with pancytopenia and infection. CONCLUSION: Single-agent fludarabine phosphate is active in previously untreated LPC lymphoma and WM, with only moderate activity in MCL. However, the CR rate is low, and the TRM is relatively high. Its role in combination chemotherapy remains to be demonstrated.

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Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenstrom's macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter's syndrome but not in common CLL

Blood ◽

10.1182/blood.v85.7.1913.bloodjournal8571913 ◽

1995 ◽

Vol 85 (7) ◽

pp. 1913-1919 ◽

Cited By ~ 76

Author(s):

H Aoki ◽

M Takishita ◽

M Kosaka ◽

S Saito

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Somatic Mutations ◽

Lymphocytic Leukemia ◽

Chain Gene ◽

Waldenström’S Macroglobulinemia ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia ◽

Richter’S Syndrome

V(D)J recombination and somatic hypermutations are developmentally regulated during B-cell differentiation; therefore, DNA analysis of the Ig gene delineates the cellular origin of B-cell neoplasms. We analyzed the third complementarity-determining region and adjacent regions of the Ig heavy-chain gene of tumor cells from 7 patients with Waldenstrom's macroglobulinemia (WM) and from 10 patients with B-cell chronic lymphocytic leukemia (CLL), 2 of whom progressed to high-grade non-Hodgkin's lymphoma (NHL), ie, Richter's syndrome (RS). There were no intraclonal variations resulting from VH replacements or ongoing somatic mutations in both WM and CLL. We found replacement mutations in the D and/or JH segments in all patients with WM and in 4 of the 10 patients with CLL, including the 2 RS patients. Replacement mutations were clustered in codon 102 of the JH segment. Preferential utilization of the JH4 gene was found in WM (5 of 7 [71.4%]) and in CLL (7 of 10 [70.0%]), and DXP family genes in CLL (5 of 10 [50.0%]). In conclusion, WM and CLL with RS are generated under the influence of antigenic stimulation and selection. However, the majority of CLL may arise from a distinct subpopulation that has the restricted repertoire of nonmutated Ig genes.

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Indolent Lymphomas: Follicular Lymphoma, HVC-Associated Marginal Zone B-Cell Lymphoma, and Waldenstrom’s Macroglobulinemia

Tropical Hemato-Oncology ◽

10.1007/978-3-319-18257-5_25 ◽

2015 ◽

pp. 245-252

Author(s):

Luca Arcaini ◽

Marzia Varettoni

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Marginal Zone ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Waldenström’S Macroglobulinemia ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Indolent Lymphomas ◽

Waldenström's Macroglobulinemia

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Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma

Oncogene ◽

10.1038/sj.onc.1201764 ◽

1998 ◽

Vol 16 (14) ◽

pp. 1891-1897 ◽

Cited By ~ 110

Author(s):

Stephan Stilgenbauer ◽

Jeremy Nickolenko ◽

Jens Wilhelm ◽

Stephan Wolf ◽

Sandra Weitz ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tumor Suppressor ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Tumor Suppressor Gene ◽

Cell Lymphoma ◽

Suppressor Gene ◽

Lymphocytic Leukemia ◽

Mantle Cell ◽

Cell Chronic Lymphocytic Leukemia

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Mantle cell lymphoma and chronic lymphocytic leukemia: report of a rare disease association and review of the literature

Journal of Hematopathology ◽

10.1007/s12308-010-0065-5 ◽

2010 ◽

Vol 3 (2-3) ◽

pp. 91-99 ◽

Cited By ~ 2

Author(s):

Joana Perdigão ◽

Helena Alaiz ◽

Paulo Lúcio ◽

Paula Gameiro ◽

Marta Sebastião ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Mantle Cell Lymphoma ◽

Rare Disease ◽

Cell Lymphoma ◽

Disease Association ◽

Lymphocytic Leukemia ◽

Review Of The Literature ◽

Mantle Cell

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Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions

Blood ◽

10.1182/blood-2017-10-764373 ◽

2018 ◽

Vol 131 (21) ◽

pp. 2283-2296 ◽

Cited By ~ 43

Author(s):

Xose S. Puente ◽

Pedro Jares ◽

Elias Campo

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Variable Region ◽

Lymphocytic Leukemia ◽

Variable Load ◽

Genomic Alterations ◽

Clinical Evolution ◽

Mantle Cell ◽

Epidemiological Characteristics

Abstract Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are 2 well-defined entities that diverge in their basic pathogenic mechanisms and clinical evolution but they share epidemiological characteristics, cells of origin, molecular alterations, and clinical features that differ from other lymphoid neoplasms. CLL and MCL are classically considered indolent and aggressive neoplasms, respectively. However, the clinical evolution of both tumors is very heterogeneous, with subsets of patients having stable disease for a long time whereas others require immediate intervention. Both CLL and MCL include 2 major molecular subtypes that seem to derive from antigen-experienced CD5+ B cells that retain a naive or memory-like epigenetic signature and carry a variable load of immunoglobulin heavy-chain variable region somatic mutations from truly unmutated to highly mutated, respectively. These 2 subtypes of tumors differ in their molecular pathways, genomic alterations, and clinical behavior, being more aggressive in naive-like than memory-like–derived tumors in both CLL and MCL. The pathogenesis of the 2 entities integrates the relevant influence of B-cell receptor signaling, tumor cell microenvironment interactions, genomic alterations, and epigenome modifications that configure the evolution of the tumors and offer new possibilities for therapeutic intervention. This review will focus on the similarities and differences of these 2 tumors based on recent studies that are enhancing the understanding of their pathogenesis and creating solid bases for new management strategies.

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