piperidines and Hodgkin-Disease

Topics: Adenine; Hodgkin Disease; Humans; Lymphocytes; Neoplasm Recurrence, Local; Piperidines

Piperazinedione given iv once every 3-4 weeks at a starting dose of 9-12 mg/m2 (4.5-12 mg/m2 for patients with myeloma) was evaluated in a Southwest Oncology Group phase II study for patients with far-advanced refractory lymphoma or multiple myeloma. Among 36 patients fully evaluable for tumor response (adequate trial), partial responses were observed in five (71%) of seven patients with Hodgkin's disease, in three (19%) of 16 patients with non-Hodgkin's lymphoma, and in none of 13 patients with multiple myeloma. Response was observed by the time of the second (five patients) or third (three patients) course. The median duration of response was 3.7 months (range, 1-17+ months). The dose-limiting toxic effects were hematologic, with 18 (50%) of 36 patients evaluable for toxicity experiencing severe leukopenia (wbc count less than 2000/mm3) and 22 (61%) experiencing severe thrombocytopenia (platelet count less than 50,000/mm3). Twenty patients had a decrease from their pretreatment hemoglobin level of greater than or equal to 2 g/100 ml. Hematologic toxic effects were often unpredictable and in several patients quite prolonged. This study indicates that piperazinedione had definite antitumor activity in patients with Hodgkin's disease and further trials in this disease using the drug at a reduced dose in combination with other effective drugs appear warranted.

Topics: Antibiotics, Antineoplastic; Clinical Trials as Topic; Drug Evaluation; Hodgkin Disease; Humans; Leukopenia; Lymphoma; Multiple Myeloma; Piperazines; Piperidines; Thrombocytopenia

Richter syndrome (RS) represents the development of high-grade lymphoma in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) and presents a diagnostic and therapeutic challenge with an adverse prognosis. The genetic background and morphology of RS in CLL patients treated with chemoimmunotherapy is extensively characterised; however, our knowledge about RS in patients treated with targeted oral therapies should be extended. To understand the morphologic and molecular changes leading to RS in CLL patients treated with the Bruton's tyrosine kinase inhibitor, ibrutinib, and the BCL2 inhibitor, venetoclax, sequential samples from six CLL/SLL patients undergoing RS were collected in both the CLL and RS phases. A detailed immunophenotypic analysis of formalin-fixed, paraffin-embedded tissue specimens of RS phase was performed, followed by extensive molecular characterisation of CLL and RS samples, including the immunoglobulin heavy chain gene (IGH) rearrangement, TP53 mutations, drug-induced resistance mutations in BTK and BCL2 genes and various copy number changes and point mutations detectable with multiplex ligation-dependent probe amplification (MLPA). Rare, non-diffuse large B-cell lymphoma phenotypes of RS were observed in 3/6 cases, including plasmablastic lymphoma and a transitory entity between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. The majority of cases were clonally related and harboured an unmutated variable region of the immunoglobulin heavy chain gene. Abnormalities affecting the TP53 gene occurred in all patients, and every patient carried at least one genetic abnormality conferring susceptibility to RS. In the background of RS, 2/5 patients treated with ibrutinib showed a BTK C481S resistance mutation. One patient developed a BCL2 G101V mutation leading to venetoclax resistance and RS. In conclusion, our findings contribute to better understanding of RS pathogenesis in the era of targeted oral therapies. Rare phenotypic variants of RS do occur under the treatment of ibrutinib or venetoclax, and genetic factors leading to RS are similar to those identified in patients treated with chemoimmunotherapy. To our best knowledge, we have reported the first BCL2 G101V mutation in an RS patient treated with venetoclax.

Topics: Adenine; Adult; Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Genes, p53; Hodgkin Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Mutation; Piperidines; Prognosis; Proto-Oncogene Proteins c-bcl-2; Risk Factors; Sulfonamides

A 71-year-old woman with a four-year history of chronic lymphocytic leukemia (CLL) received ibrutinib as initial treatment due to progressive anemia and thrombocytopenia. Eleven months after the start of the treatments, although her cytopenia had ameliorated, she developed classic Hodgkin lymphoma, a rare form of Richter's transformation. She was successfully treated with two courses of adriamycin, vinblastin, bleomycin and dacarbazine followed by radiotherapy. In general, several clinical, genetic and molecular factors are associated with Richter's transformation. In addition, our present case suggested that ibrutinib could be a potential risk factor for Richter's transformation in CLL patients.

Topics: Adenine; Aged; Female; Hodgkin Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Transplantation Conditioning; Transplantation, Homologous

Topics: Adenine; Adult; Hodgkin Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Piperidines; Poland; Pyrazoles; Pyrimidines

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Allografts; Autografts; Azetidines; B-Lymphocytes; Cell Separation; Drug Approval; Fetal Blood; Graft vs Host Disease; Hodgkin Disease; Humans; Nitriles; Photopheresis; Piperidines; Problem Solving; Purines; Pyrazoles; Pyrimidines; Stem Cell Transplantation; Sulfonamides; T-Lymphocytes, Regulatory; United States; United States Food and Drug Administration

The established treatment algorithms for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are currently challenged by novel classes of drugs, with ibrutinib being one of the most effective. Published data suggest that patients with early progression under ibrutinib often emerge as having Richter's transformation (RT) with a rapidly fatal prognosis, mostly developing diffuse large B-cell lymphoma (DLBCL). In this respect, it is known that RT to large DLBCL occurs in about 5% of patients with CLL during the disease course and less frequently to Hodgkin lymphoma (HL). Here, we report a patient with CLL who presented with HL transformation while still receiving therapy with ibrutinib stressing the need for clinical vigilance in any case with persisting or enlarging lymph nodes during treatment with this agent, as prompt modification of therapy is most important.

Topics: Adenine; Aged; Antineoplastic Agents; Biopsy; Cell Transformation, Neoplastic; Disease Progression; Hodgkin Disease; Humans; Immunohistochemistry; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed; Treatment Outcome

Chronic lymphocytic leukaemia (CLL) is a chronic B-cell lympho-proliferative disorder in which lymphomatous transformations occur in 5%-15% of patients. Histologically these cases resemble diffuse large B-cell lymphoma, or Richter's transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67-year-old female with CLL treated with the novel Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno-histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Marrow; Fatal Outcome; Female; Hodgkin Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms, Second Primary; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Male; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Radionuclide Imaging

Cannabinoid receptor 1 (CB1) is expressed in certain types of malignancies. An analysis of CB1 expression and function in Hodgkin lymphoma (HL), one of the most frequent lymphomas, was not performed to date.. We examined the distribution of CB1 protein in primary cases of HL. Using lymphoma derived cell lines, the role of CB1 signaling on cell survival was investigated.. A predominant expression of CB1 was found in Hodgkin-Reed-Sternberg cells in a vast majority of classical HL cases. The HL cell lines L428, L540 and KM-H2 showed strong CB1-abundance and displayed a dose-dependent decline of viability under CB1 inhibition with AM251. Further, application of AM251 led to decrease of constitutively active NFκB/p65, a crucial survival factor of HRS-cells, and was followed by elevation of apoptotic markers in HL cells.. The present study identifies CB1 as a feature of HL, which might serve as a potential selective target in the treatment of Hodgkin lymphoma.

Topics: Apoptosis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Hodgkin Disease; Humans; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Signal Transduction; Transcription Factor RelA