idelalisib and Chromosome-Deletion

Two major advances were made in the treatment of chronic lymphocytic leukaemia (CLL): the addition of the antibody rituximab to chemotherapy two decades ago and the introduction of the targeted agents during the last few years. Four targeted drugs with different mechanisms of action were added to the armamentarium of CLL treatment: the anti-CD20 antibody obinutuzumab, the two kinase inhibitors ibrutinib and idelalisib, which target the Bruton tyrosine kinase (BTK) and Phosphatidylinositiol-3-Kinase (PI3K) respectively in the B-cell receptor signalling pathway, as well as the Bcl2-antagonist venetoclax.Recently, the combination of venetoclax/obinutuzumab was approved for the first-line treatment of all CLL patients based on a phase-III trial in elderly unfit patients. This combination was shown to be clearly superior to chlorambucil/obinutuzumab and should become the preferred first-line treatment for the so called "slow-go" patients. Other options for these elderly, unfit patients are continuous ibrutinib or chlorambucil/obinutuzumab. Although data from phase-III studies are not yet available, venetoclax/obintuzumab may also be offered to younger, fit patients. Established therapeutic options for these so called "go go" patients are ibrutinib, fludarabin/cyclophosphamide/rituximab or bendemustine/rituximab (if > 65 years). Patients with the high-risk parameters deletion 17p or TP53mutation are known to poorly respond to chemo(immuno)therapy and should receive either ibrutinib or venetoclax/obinutuzumab.Thus, a choice has to be made between a continuous monotherapy with ibrutinib or a time-limited combination with either venetoclax/obinutuzumab (12 months) or chemoimmunotherapy (usually 6 months). In addition to disease-related factors (e. g. presence of deletion 17p/TP53 mutation, IgHV mutational status, prior therapies), comorbidities, co-medication and the specific side effects of the CLL therapies (myelosuppression, infections and secondary malignancies for chemoimmunotherapy; cardiac toxicity, bleeding and autoimmune disease for ibrutinib; tumour-lysis syndromes and infections for venetoclax) the patient's expectations need to be considered.. Die Aktualisierung der IWCLL-Kriterien ließ die Kriterien für die Diagnosestellung der CLL unberührt: In der Regel genügt weiterhin ein Blutausstrich und eine Immunphänotypisierung.. Auch die Kriterien für die Therapieeinleitung blieben unverändert: Nur Patienten mit symptomatischer, fortgeschrittener Erkrankung sollen behandelt werden. Die Untersuchung auf Vorliegen einer Deletion 17p und/oder TP53-Mutation als wichtigster ungünstiger Prognosefaktor und prädiktiver Faktor ist essenziell vor Einleitung jeder neuen Therapie. Die Bedeutung des Mutationsstatus der variablen Region des Immunglobulin-Schwerkettengens (IgHV) hat deutlich zugenommen.. Die Kombination des Bcl2-Antagonisten Venetoclax mit dem Antikörper Obinutuzumab wurde kürzlich für die Erstlinientherapie der CLL zugelassen. Aufgrund der klaren Überlegenheit gegenüber Chlorambucil/Obinutuzumab bei den unfitten, älteren Patienten sollte Venetoclax/Obinutuzumab von nun an die bevorzugte Behandlungsoption bei dieser Patientengruppe sein. Als Chemotherapie-freie und zeitlich limitierte Behandlung wird Venetoclax/Obinutuzumab auch bei den Hochrisikopatienten mit Deletion 17p/TP53-Mutation und bei den jüngeren, fitten Patienten künftig eine wichtige Option neben der Dauertherapie mit Ibrutinib darstellen. Bei Letzteren kann bei Vorliegen eines mutierten IgHV-Status auch eine Chemoimmuntherapie mit Rituximab, kombiniert mit Fliudarabin/Cyclophosphamid oder Bendamustin, erfolgen.. Auch in der Rezidiv-Situation werden vorzugsweise die zielgerichteten Substanzen eingesetzt unter Berücksichtigung der zyto- und molekulargenetischen Risikofaktoren der CLL, der Patientencharakteristiken, der Tiefe und Dauer des Ansprechens sowie Verträglichkeit der vorangegangenen Therapie(n).

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Comorbidity; Drug Approval; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Staging; Piperidines; Prognosis; Purines; Quinazolinones; Rituximab; Smith-Magenis Syndrome; Sulfonamides

With the recent approval of several effective and well-tolerated novel agents (NAs), including ibrutinib, idelalisib, venetoclax, and obinutuzumab, patients with chronic lymphocytic leukemia (CLL) have more therapeutic options than ever before. The availability of these agents is both an important advance for patients but also a challenge for practicing hematologist/oncologists to learn how best to sequence NAs, both with respect to chemoimmunotherapy (CIT) and to other NAs. The sequencing of NAs in clinical practice should be guided both by an individual patient's prognostic markers, such as FISH and immunoglobulin heavy chain variable region (

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Smith-Magenis Syndrome; Sulfonamides

Chronic lymphocytic leukaemia (CLL) frequently responds to chemoimmunotherapy combining cytotoxic chemotherapy and monoclonal antibodies. However, CLL is associated with significant genetic heterogeneity, and some high-risk forms are known to be chemo-resistant and associated with early relapse.. To review the current treatment paradigm of patients with high-risk disease, in particular those with del(17p) and TP53 variants.. A 'watch and wait' approach is recommended for all patients who are asymptomatic. When symptomatic, fluorescence in situ hybridisation testing should be performed and gene sequencing considered subsequently to identify del(17p) and TP53 variants respectively. In the front-line setting, treatment within a clinical trial is the preferred option. In the relapsed or refractory setting, patients with del(17p) or TP53 aberrations should be offered treatment with a novel agent, such as ibrutinib, idelalisib-rituximab or venetoclax. However, of note, at the date of this publication venetoclax is not PBS reimbursed, and ibrutinib will not be reimbursed until 1 December 2017.. Testing for del(17p) and TP53 variants identifies high-risk CLL that requires specialist management.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Australia; Chromosome Deletion; Chromosomes, Human, Pair 17; Guidelines as Topic; Humans; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Purines; Quinazolinones; Rituximab; Tumor Suppressor Protein p53; Watchful Waiting

Splenic marginal zone lymphoma (SMZL) is a rare indolent B-cell malignancy involving the spleen and bone marrow. Various cytogenetic abnormalities with prognostic value have been identified in SMZL. Complexity of karyotype, 14q aberrations, and

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Marrow; Chromosome Deletion; Chromosomes, Human, Pair 17; Cytogenetic Analysis; Diagnostic Imaging; Female; Humans; Immunophenotyping; Lymphoma, B-Cell, Marginal Zone; Neoplasm Staging; Purines; Quinazolinones; Rituximab; Splenic Neoplasms; Treatment Outcome