scholarly journals HSV-1 Encephalitis in an Elderly Man Receiving Ibrutinib for Waldenstrom’s Macroglobulinemia

2020 ◽  
Vol 2020 ◽  
pp. 1-2
Author(s):  
Mark R. Wallace
Keyword(s):  
Fungal Infections ◽  
Major Complication ◽  
Hepatitis E ◽  
Lymphocytic Leukemia ◽  
Waldenström’S Macroglobulinemia ◽  
Herpes Encephalitis ◽  
Mantle Cell ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström'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.

scholarly journals 1130. Low Risk of Pneumocystis jiroveci Pneumonia in Patients With Waldenstrom’s Macroglobulinemia on Ibrutinib

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S338-S339
Author(s):  
Amanda E Kusztos ◽  
Matthew P Cheng ◽  
Joshua N Gustine ◽  
Toni E Dubeau ◽  
Ann E Woolley ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Lymphocytic Leukemia ◽  
Waldenström’S Macroglobulinemia ◽  
Pneumocystis Jiroveci ◽  
Pneumocystis Jiroveci Pneumonia ◽  
Increased Risk ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Research Grant

Abstract Background Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA approved for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom’s macroglobulinemia (WM). Fungal infections including Pneumocystis jiroveci pneumonia (PCP) are increasingly reported in patients with CLL and lymphoma on ibrutinib possibly due to the off-target effect of ibrutinib on the adaptive immune system. Whether this increased risk is due to the effect of ibrutinib alone or in combination with immune dysregulation due to underlying malignancy is unknown. The purpose of this study was to assess the incidence of PCP in patients with WM on ibrutinib therapy. Methods A retrospective cohort study was performed of all patients with WM who initiated ibrutinib monotherapy at Dana-Farber Cancer Institute between July 1, 2015 and January 30, 2018. Baseline characteristics, laboratory parameters, previous and concomitant malignancy treatment regimens, and antimicrobial medications were collected by chart review. Patients were followed until April 1, 2018 for the development of PCP. Results There were a total of 106 patients with WM on ibrutinib during the study period. Sixty-one (58%) were male, and the median age at initiation of ibrutinib was 69 years (range 43 – 89). Forty-six patients (43%) received prior therapy for WM, with a median of two previous treatment courses (range 1–6). Fourteen patients (13%) were on PCP prophylaxis for a combined duration of 8 person-years. No cohort patient developed PCP during the study period, which included 146 person-years of ibrutinib exposure. Three patients (3%) died due to disease progression (n = 2) and E. coli sepsis (n = 1). Conclusion Patients with WM on ibrutinib monotherapy appear to have a different infectious risk profile than patients with CLL or lymphoma and do not have a high risk of developing PCP. These data suggest that PCP prophylaxis is likely not beneficial for patients with WM on ibrutinib. Disclosures M. P. Cheng, Royal College of Physicians and Surgeons of Canada: Member, Salary. S. P. Hammond, Merck: Investigator, Research support. J. J. Castillo, Pharmacyclics: Consultant and Grant Investigator, Consulting fee and Research grant. N. C. Issa, GSK: Investigator, Research grant. Merck: Investigator, Research grant. Akros Pharma: Consultant, Consulting fee.

scholarly journals Idiotypic cross-reactivity of immunoglobulins expressed in Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia, and mantle zone lymphocytes of secondary B-cell follicles

Blood ◽  
1991 ◽  
Vol 77 (7) ◽  
pp. 1484-1490 ◽  
Author(s):  
O Axelrod ◽  
GJ Silverman ◽  
V Dev ◽  
R Kyle ◽  
DA Carson ◽  
...  
Keyword(s):  
B Cell ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Waldenström’S Macroglobulinemia ◽  
Mantle Zone ◽  
Human Tonsil ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Monoclonal antibodies (MoAbs) specific for autoantibody-associated cross-reactive idiotypes (CRIs) of Waldenstrom's IgM react frequently with the surface Ig (slg) expressed by leukemia cells of patients with chronic lymphocytic leukemia (CLL). Evaluation of the molecular basis for this cross-reactivity indicates that such CRIs are encoded by conserved antibody variable region genes (V genes) that have undergone little or no somatic hypermutation. We find that such anti-CRI MoAbs stain a subpopulation of cells within the mantle zones surrounding the germinal centers of normal human tonsil. In contrast, MoAbs specific for variable region subgroup determinants react with cells in both the mantle zones and germinal centers of secondary B-cell follicles. To test whether mantle zone B cells not reactive with existing anti-CRI MoAbs may express slg bearing as-yet-unrecognized CRIs present on Igs produced by neoplastic cells of some patients with Waldenstrom's macroglobulinemia or CLL, we immunized mice with purified Waldenstrom's IgM that have been characterized for their variable region subgroups using subgroup-specific antisera raised against synthetic peptides. The supernatants of hybridomas generated from the splenocytes of immunized mice were screened for their ability to stain a subpopulation of mantle zone lymphocytes in human tonsil. With this approach, two new anti-CRI MoAbs were identified, designated OAK1 and VOH3. OAK1 binds to a CRI present on a subset of kappa light chains of the VK1 subgroup. VOH3 recognizes a CRI determinant(s) present on a subset of antibody heavy chains of the VH3 subgroup. Flow cytometric analyses demonstrated that OAK1 specifically binds leukemia cells from 5 to 20 patients (25%) with kappa light chain expressing CLL. In addition, VOH3 reacted with the leukemia cells from 1 of 17 (6%) patients tested. The success of these methods demonstrates that the variable regions of the Igs produced by mantle zone B cells share idiotypic determinants with Igs expressed in B-cell CLL (B-CLL) and Waldenstrom's macroglobulinemia.

Clinical Responses to Sildenafil in Waldenstrom’s Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4926-4926 ◽  
Author(s):  
Steven P. Treon ◽  
Olivier Tournilhac ◽  
Andrew Branagan ◽  
Zachary Hunter ◽  
Lian Xu ◽  
...  
Keyword(s):  
B Cell ◽  
Phosphodiesterase Inhibitor ◽  
Phosphodiesterase Inhibitors ◽  
Fold Increase ◽  
Lymphocytic Leukemia ◽  
Waldenström’S Macroglobulinemia ◽  
Institutional Review ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Waldenstrom’s macroglobulinemia (WM) is an incurable B-cell malignancy. Interestingly, we have observed unusual response activity in five WM patients which appears related to their use of sildenafil, a phosphodiesterase inhibitor used to treat erectile dysfunction. One patient demonstrated a complete remission, while four other patients demonstrated less dramatic, but also unexpected responses associated with sildenafil used at doses of 25–50 mg once to twice a week. In view of these observations, we next evaluated sildenafil for its ability to induce apoptosis of lymphoplasmacytic cells obtained from WM patients. All patients provided written consent for this study which was approved by our institutional review board. Sorted (CD19+, light chain restricted) bone marrow lymphoplasmacytic cells obtained from 6 WM patients were cultured in media alone or with sildenafil (kindly provided by Pfizer Pharmaceuticals, Inc.) at 0.01 ug/ml for 24 hours. These studies demonstrated a mean 2.1 (range 1.24–4.8) fold increase in sildenafil specific/spontaneous apoptosis in lymphoplasmacytic cells from 5 of 5 patients, which included those from a patient who demonstrated a clinical response to sildenafil. Importantly, the concentrations at which apoptosis was observed in these studies is within pharmacologically achievable levels for sildenafil. The results of these studies, along with those recently reported by Sarfati et al (Blood 101:265) who demonstrated caspase mediated apoptosis of B-chronic lymphocytic leukemia (CLL) cells by sildenafil, provide the framework for investigation of sildenafil and related phosphodiesterase inhibitors in the treatment of WM and other B-cell malignancies.

scholarly journals Idiotypic cross-reactivity of immunoglobulins expressed in Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia, and mantle zone lymphocytes of secondary B-cell follicles

Blood ◽  
1991 ◽  
Vol 77 (7) ◽  
pp. 1484-1490
Author(s):  
O Axelrod ◽  
GJ Silverman ◽  
V Dev ◽  
R Kyle ◽  
DA Carson ◽  
...  
Keyword(s):  
B Cell ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Waldenström’S Macroglobulinemia ◽  
Mantle Zone ◽  
Human Tonsil ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Monoclonal antibodies (MoAbs) specific for autoantibody-associated cross-reactive idiotypes (CRIs) of Waldenstrom's IgM react frequently with the surface Ig (slg) expressed by leukemia cells of patients with chronic lymphocytic leukemia (CLL). Evaluation of the molecular basis for this cross-reactivity indicates that such CRIs are encoded by conserved antibody variable region genes (V genes) that have undergone little or no somatic hypermutation. We find that such anti-CRI MoAbs stain a subpopulation of cells within the mantle zones surrounding the germinal centers of normal human tonsil. In contrast, MoAbs specific for variable region subgroup determinants react with cells in both the mantle zones and germinal centers of secondary B-cell follicles. To test whether mantle zone B cells not reactive with existing anti-CRI MoAbs may express slg bearing as-yet-unrecognized CRIs present on Igs produced by neoplastic cells of some patients with Waldenstrom's macroglobulinemia or CLL, we immunized mice with purified Waldenstrom's IgM that have been characterized for their variable region subgroups using subgroup-specific antisera raised against synthetic peptides. The supernatants of hybridomas generated from the splenocytes of immunized mice were screened for their ability to stain a subpopulation of mantle zone lymphocytes in human tonsil. With this approach, two new anti-CRI MoAbs were identified, designated OAK1 and VOH3. OAK1 binds to a CRI present on a subset of kappa light chains of the VK1 subgroup. VOH3 recognizes a CRI determinant(s) present on a subset of antibody heavy chains of the VH3 subgroup. Flow cytometric analyses demonstrated that OAK1 specifically binds leukemia cells from 5 to 20 patients (25%) with kappa light chain expressing CLL. In addition, VOH3 reacted with the leukemia cells from 1 of 17 (6%) patients tested. The success of these methods demonstrates that the variable regions of the Igs produced by mantle zone B cells share idiotypic determinants with Igs expressed in B-cell CLL (B-CLL) and Waldenstrom's macroglobulinemia.

scholarly journals 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 ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1913-1919 ◽  
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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