pci-32765 and Syndrome

Over the last decade, there have been important developments in the treatment of lymphoproliferative disorders. Apart from conventional chemotherapy, a wide array of therapies has been developed, with different indications. The aim of this review is to evaluate the risk of infection associated with these therapies, as well as establishing prevention recommendations. In all cases, the patient's underlying disease as well as concomitant or previous therapies have an impact on the risk of infection. Anti-CD20 antibodies (rituximab, ofatumumab and obinutuzumab) have been associated with a higher risk of bacterial and viral infection, as well as reactivation of latent infections and opportunistic infections. Alemtuzumab is associated with severe, protracted immunosuppression. Ibrutinib and acalabrutinib have been linked to bacterial infections (especially respiratory infections), invasive fungal infections and opportunistic infections. Idelalisib carries a higher risk of Pneumocystis jirovecii and infection and cytomegalovirus reactivation. Venetoclax is associated with respiratory infections and neutropenia. Immune checkpoint inhibitors are not directly associated with a higher risk of infection; nevertheless, the use of corticosteroids and immunosuppressants to control immune-related adverse events results in an increase of the risk of infection. Brentuximab, lenalidomide and histone deacetylase inhibitors do not seem to be associated with a higher risk of infections. Although data are scarce, a higher number of infections have been observed with cellular therapies, mostly in patients with more than 3 previous antineoplastic treatments or those receiving tocilizumab or corticosteroids for managing the cytokine release syndrome. In all patients, we recommend appropriate vaccination, screening for latent infections, and individualized prophylaxis recommendations.

Topics: Adenine; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Communicable Disease Control; Humans; Immune Checkpoint Inhibitors; Infections; Lymphoproliferative Disorders; Piperidines; Purines; Pyrazines; Quinazolinones; Risk; Rituximab; Sulfonamides; Syndrome

Bing-Neel syndrome (BNS) is characterised by infiltration of the central nervous system by lymphoplasmacytic lymphoma (LPL) cells and is traditionally regarded as a complication of pre-existing systemic Waldenström's macroglobulinaemia (WM). We describe the case of a 49 year old woman with leptomeningeal LPL who did not fulfil diagnostic criteria for concomitant systemic WM at presentation, and who failed to respond to conventional chemotherapy treatment (including high dose methotrexate) but did respond to the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib. This highlights an important variation in the typical natural history of this rare disease and also further supplements emerging evidence regarding efficacy of ibrutinib in its treatment.

Topics: Adenine; Female; Humans; Lymphoma; Meningeal Carcinomatosis; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Syndrome

Ibrutinib is a tyrosine kinase inhibitor commonly used in patients with chronic lymphocytic leukemia. Based on the published literature, it has a very sound ophthalmologic safety profile. In the following, we describe a case of anterior chamber fibrinoid syndrome in a patient on ibrutinib for B-cell chronic lymphocytic leukemia after uncomplicated cataract extraction.. A 75-year-old white man with B-cell chronic lymphocytic leukemia on ibrutinib therapy and without significant past ocular history presented 1 day after uncomplicated phacoemulsification with in-the-bag intraocular lens implantation with multiple, discrete, pigmented cords in the anterior chamber. His vision was 20/100 and intraocular pressure was 43 mmHg. There was no hypopyon, hyphema, or cellular reaction. The dilated fundus examination was unremarkable. He was diagnosed as having fibrinoid syndrome and started on topical prednisolone, brimonidine, timolol-dorzolamide, and orally administered acetazolamide. Within 2 weeks, the fibrin cords disappeared completely, vision improved to 20/30, and the intraocular pressure normalized off all medications.. The precise etiology of fibrinoid syndrome remains unclear. This is the first case of fibrinoid syndrome in a patient on ibrutinib, which is known to cross the blood-brain barrier and induce intraocular changes. It is important to differentiate this syndrome from toxic anterior segment syndrome and endophthalmitis, and to initiate appropriate treatment. The fibrin bands tend to be exquisitely sensitive to topical steroids and to resolve within a few weeks without sequelae.

Topics: Adenine; Administration, Topical; Aged; Anterior Chamber; Antihypertensive Agents; Antineoplastic Agents; Brimonidine Tartrate; Cataract Extraction; Humans; Intraocular Pressure; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Phacoemulsification; Piperidines; Prednisolone; Pyrazoles; Pyrimidines; Sulfonamides; Syndrome; Thiophenes; Timolol; Treatment Outcome; Visual Acuity

Topics: Adenine; Aged; Brain Diseases; Central Nervous System Neoplasms; Female; Humans; Immunotherapy; Piperidines; Syndrome

NOTCH1 mutations in chronic lymphocytic leukemia (CLL) lead to accumulation of NOTCH1 intracellular domain (NICD) and prolong signaling. These mutations associate with a more aggressive disease compared to wild-type (WT) CLL. In this work we demonstrate a bidirectional functional relationship between NOTCH1 and the B cell receptor (BCR) pathways. By using highly homogeneous cohorts of primary CLL cells, activation of NOTCH1 is shown to increase expression of surface IgM, as well as LYN, BTK, and BLNK, ultimately enhancing BCR signaling responses, including global mRNA translation. Upon BCR cross-linking, NOTCH1 itself is actively translated and increased on cell surface. Furthermore, BCR ligation induces calcium mobilization that can facilitate ligand-independent NOTCH1 activation. These data suggest that the two pathways are functionally linked, providing a rationale for dual inhibition strategies. Consistently, addition of the γ-secretase inhibitor DAPT to ibrutinib significantly potentiates its effects, both in vitro and in a short-term patient-derived xenograft model. While this observation may find limited applications in the CLL field, it is more relevant for Richter's Syndrome (RS) management, where very few successful therapeutic options exist. Treatment of RS-patient-derived xenografts (RS-PDX) with the combination of ibrutinib and DAPT decreases disease burden and increases overall survival.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases; Animals; Calcium; Diamines; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Receptor, Notch1; Receptors, Antigen, B-Cell; Signal Transduction; Syndrome; Thiazoles

Topics: Adenine; Adolescent; Agammaglobulinaemia Tyrosine Kinase; Female; Humans; Myeloid Differentiation Factor 88; Piperidines; Syndrome; Waldenstrom Macroglobulinemia

The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.

Topics: Adenine; Adult; Aged; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Bing-Neel syndrome is a rare complication of Waldenström macroglobulinemia, characterized by infiltration of lymphoplasmacytic cells to the central nervous system. Multiple treatment modalities exist including purine analogs, bendamustine, high-dose methotrexate, or high-dose cytarabine. Of interest, ibrutinib, a Bruton tyrosine kinase inhibitor has also displayed efficacy in Bing-Neel syndrome. Current literature is limited for the treatment of Bing-Neel syndrome considering its rarity, and while ibrutinib is indicated for the treatment of Waldenström macroglobulinemia, it is utilized off-label for treatment of Bing-Neel syndrome. Additionally, debate exists regarding the recommended dosing strategy for ibrutinib for this indication with disease remission demonstrated at 560 mg and 420 mg. We present a case report that provides additional evidence for this debate with a patient who received 560 mg of ibrutinib initially and maintained disease control despite a dose reduction to 420 mg for tolerability. Ultimately, more data are needed to develop standardized Bing-Neel syndrome treatment strategies with specific consideration to the use of ibrutinib in this condition.

Topics: Adenine; Brain Diseases; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Waldenstrom's macroglobulinaemia (WM) is a lymphoproliferative disorder of the B cell origin. It is characterised by the presence of IgM paraprotein in the serum and lymphoplasmacytic lymphoma cells in the bone marrow with extranodal involvement relatively uncommon. Bing-Neel syndrome (BNS) is a neurological complication of WM that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. We present an interesting case of BNS that responded remarkably to ibrutinib monotherapy.

Topics: Adenine; Brain; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Mutation; Myeloid Differentiation Factor 88; Neurodegenerative Diseases; Piperidines; Pyrazoles; Pyrimidines; Syndrome; Waldenstrom Macroglobulinemia

Topics: Adenine; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Syndrome

Topics: Adenine; Aged; Brain; Brain Diseases; Humans; Magnetic Resonance Imaging; Male; Piperidines; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Richter syndrome (RS) is a rare event in chronic lymphocytic leukemia (CLL) that is influenced by biological factors and prior CLL treatments. Ibrutinib is a Bruton tyrosine kinase inhibitor that has shown remarkable efficacy in CLL; however, little is known about its relationship to RS. We report a case of ibrutinib efficacy against CLL in a patient with prolonged remission of RS.. The patient was diagnosed with CLL in 2003. Biological findings at onset included absent ZAP70 expression, mutated IGVH, and NOTCH1 mutation. He was treated with FCR with partial response. In 2013, he progressed to RS, not clonally related to the underlying CLL. The patient was treated with anthracycline- and platinum-based regimens, obtaining a complete remission. After 3 years, he presented a CLL progression with worsening lymphocytosis, anemia, thrombocytopenia, increased splenomegaly, and lymphadenopathies. Positron emission tomography-computed tomography scan excluded pathologic uptake. Thus, he was started on ibrutinib.. At 12 months' follow-up, we observed white blood cell normalization, increased hemoglobin and platelet levels, disappearance of lymphadenopathy, and spleen size reduction. Therapy was well-tolerated with no evidence of RS.. This case demonstrates sustained RS remission in a patient with CLL under ibrutinib therapy, thus improving our knowledge on the use of this new drug in CLL and beyond.

Topics: Adenine; Aged; Cell Transformation, Neoplastic; Disease Progression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Syndrome

Topics: Adenine; Animals; Antibodies; Antigens, CD19; Cytokines; Heterografts; Humans; Lymphoma, B-Cell; Mice; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, Antigen, T-Cell; Recombinant Fusion Proteins; Syndrome

Topics: Adenine; Aged; Amiodarone; Atrial Fibrillation; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Heart Failure; Humans; Male; Piperidines; Pyrazoles; Pyrimidines; Syndrome

Topics: Adenine; Aged; Central Nervous System Diseases; Female; Humans; Immunoglobulin M; Leukocyte Count; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Piperidines; Prednisone; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Rituximab; Syndrome; Vincristine