piperidines and Hematologic-Diseases

Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) in 2014. Ibrutinib is often used to treat patients who are younger than the patients originally included in theclinical trials have additional unfavorable prognostic factors and suffer from additional comorbidities excluded from the original phase III trials. Our objective was to examine current clinical practices and their impact in this expanded population of CLL patients who often require adjustments in the standard prescribed dose and schedule of therapy.. An extensive review of the medical literature was conducted to establish the consensus on ibrutinib dose modifications in patients with CLL. Twenty-nine studies were reviewed including fourteen clinical trials and fifteen "real-world practice" studies.. The average discontinuation rate was similar between clinical trials and "real-world practice" studies though the reasons for discontinuation differed. CLL progression was a more common reason for discontinuation in clinical trial studies while toxicity was a more common reason for discontinuation in "real-world practice" studies. Some studies have suggested worse outcomes in patients requiring dose reductions in ibrutinib while others have shown no change in treatment efficacy in patients requiring dose reductions due to concomitant CYP medications or increased immunosuppression post-transplant.. The impact of ibrutinib dose modifications on clinical outcome remains unclear. Patients on concomitant CYP3A inhibitors should be prescribed a lower dose than the standard 420 mg daily, in order to maintain comparable pharmacologic properties. Further research is required to establish definitive clinical practice guidelines.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Biotransformation; Clinical Studies as Topic; Clinical Trials as Topic; Cohort Studies; Cytochrome P-450 CYP3A; Disease Susceptibility; Dose-Response Relationship, Drug; Early Termination of Clinical Trials; Hematologic Diseases; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Proteins; Pilot Projects; Piperidines; Practice Patterns, Physicians'; Protein Kinase Inhibitors

Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was reported, and venetoclax at 400 mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events. The complete response rate assessed by positron emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10/14 patients) and 100% of untreated MRD-evaluable patients (n = 12) at the end of 3 cycles. The median follow-up for relapsed patients was 17 months (range, 10-35 months). The 2-year progression-free survival (PFS) was 69.5% (95% confidence interval [CI], 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%) for overall survival. The median follow-up was 14 months (range, 5-19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5%-100%). The combination of obinutuzumab, ibrutinib, and venetoclax is well tolerated and provides high response rates, including at the molecular level, in relapsed and untreated MCL patients. This trial was registered at www.clinicaltrials.gov as #NCT02558816.

Topics: Adenine; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Female; Follow-Up Studies; Genes, p53; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm, Residual; Piperidines; Progression-Free Survival; Prospective Studies; Sulfonamides; Treatment Outcome

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Cardiovascular Diseases; Female; Follow-Up Studies; Hematologic Diseases; Humans; Infections; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Risk; Salvage Therapy; Treatment Outcome

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cytarabine; Disease-Free Survival; Etoposide; Female; Flavonoids; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Piperidines; Recurrence; Remission Induction; Salvage Therapy; Sirolimus; Topotecan; Tumor Lysis Syndrome

Topics: Adenine; Autoimmune Diseases; Disease-Free Survival; Female; Hematologic Diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Survival Rate

Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy.. Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met.. A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen).. Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872 .).

Topics: Adenine; Aged; Aged, 80 and over; Bendamustine Hydrochloride; Drug Therapy, Combination; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Progression-Free Survival; Pyrazoles; Pyrimidines; Rituximab; Survival Analysis

To evaluate the efficacy and safety of masitinib combined with gemcitabine in patients with advanced pancreatic cancer.. Twenty-two non-randomised patients with unresectable, locally advanced (n = 9) or metastatic pancreatic cancer (n = 13) received oral masitinib (9 mg/kg/day) combined with standard gemcitabine. All patients were naive to systemic chemotherapy or radiotherapy. The primary endpoint was time-to-progression (TTP) with efficacy and safety analyses performed on the intent-to-treat population. Secondary endpoints included overall survival (OS), as well as, subgroup analyses according to baseline disease, and performance status.. Overall median TTP was 6.4 months (95% CI [2.7-11.7]); 8.3 and 2.7 months, respectively, for locally advanced and metastatic patients; 6.4 and 0.8 months, respectively, for patients with KPS [80-100] or KPS [70]. Median OS was 7.1 months (95% CI [4.8-17.0]); 8.4 and 6.8 months for locally advanced or metastatic patients, respectively; 8.0 and 4.4 months in patients with KPS [80-100] or KPS [70], respectively. The 18-month observed survival rate was similar for locally advanced (22%) and metastatic patients (23%) and reached 28% for KPS [80-100] patients. The most common suspected adverse events were nausea, vomiting, rash, diarrhoea, peripheral oedema, anaemia, lymphopenia, thrombocytopenia, pyrexia, neutropenia, asthenia, leucopenia, and abdominal pain, and most were of grades 1-2 severity.. The efficacy and safety of masitinib combined with gemcitabine are encouraging, with extended survival and median TTP that support initiation of a phase 3 trial.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Endpoint Determination; Female; Gemcitabine; Hematologic Diseases; Humans; Male; Middle Aged; Pancreatic Neoplasms; Piperidines; Pyridines; Survival Analysis; Thiazoles

Ibrutinib-related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment-naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off-study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major-response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2-4] and 5·7 (95% CI: 4-12) months, respectively. The median follow-up was 19 (95% CI: 14-21) months; 18-month progression-free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3-16·7) months, and the median duration-of-response was 32 (range: 23-32) months. Twenty-five patients (31%) had discontinued therapy at last follow-up (68% due to treatment-related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial-fibrillation (11%) were common non-haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunoglobulin M; Kaplan-Meier Estimate; Male; Middle Aged; Piperidines; Practice Patterns, Physicians'; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Salvage Therapy; Treatment Outcome; Waldenstrom Macroglobulinemia

Ovarian cancer is the second most common and the most lethal gynecological malignancy in the western world. Unfortunately, there are lack of methods for early screening and diagnosis of the disease. Because of this, most of the cases are diagnosed at an advanced stage and have poor prognosis. The standard treatment of ovarian cancer is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. There are new molecular agents available for maintenance therapy of ovarian cancer including anti-angiogenic therapies, poly adenosine diphosphate ribose polymerase inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor that has shown to be clinically effective as maintenance therapy in patients with platinum sensitive, recurrent ovarian cancer. Studies have shown the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of presence or absence of BRCA gene mutations or homologous recombination deficiency status. Studies have shown that treatment-emergent Grade 3 or Grade 4 hematological events were observed in patients receiving niraparib including thrombocytopenia (33.8%), anemia (25.3%) and neutropenia (19.6%). Most of the hematological laboratory abnormalities occurred within the first three treatment cycles. After dose adjustment, the incidence of hematological abnormalities was infrequent beyond cycle 3. We are reporting two cases of Grade III/IV neutropenia and thrombocytopenia in patients treated with niraparib in our institution. Unfortunately, one of the patients succumbed to septic shock secondary to right lower lobe pneumonia while severely neutropenic. The second patient's blood counts improved after discontinuing the medication and with supportive transfusions during the hospitalization.

Topics: Aged, 80 and over; Female; Hematologic Diseases; Humans; Indazoles; Middle Aged; Mutation; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Topics: Adenine; Female; Hematologic Diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Middle Aged; Piperidines; Pyrazoles; Pyrimidines

Topics: ADAMTS13 Protein; Adenine; Antibodies, Monoclonal; Antineoplastic Agents; Central Venous Catheters; fms-Like Tyrosine Kinase 3; Genetic Therapy; Graft vs Host Disease; Hematologic Diseases; Hemophilia B; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Multiple Myeloma; Mutation; Piperidines; Protein Kinase Inhibitors; Purpura, Thrombotic Thrombocytopenic; Pyrazoles; Pyrimidines; Recombinant Proteins; Societies, Medical; Thrombosis

Topics: Adenine; Adult; Aged; Aged, 80 and over; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Hematologic Diseases; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Poland; Prognosis; Pyrazoles; Pyrimidines; Survival Rate

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Female; France; Gastrointestinal Diseases; Hematologic Diseases; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Salvage Therapy; Treatment Outcome

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin's lymphoma. It can follow a heterogeneous clinical course but generally patients relapse early after standard immunochemotherapy regimens and develop resistance to subsequent therapies. For younger patients, intensive approaches followed by autologous stem cell transplantation offer excellent long-term disease control but with the possible exception of an allogenic stem cell transplant, MCL is an incurable condition. As MCL principally affects older individuals, the majority of patients are not candidates for such intensive approaches. Ibrutinib is an orally active, Bruton's tyrosine kinase inhibitor. It inhibits signaling pathways downstream of Bruton's tyrosine kinase that appear critical for the proliferation and survival of MCL. As a single agent it has shown extremely promising activity in relapsed and refractory MCL patients with an excellent side-effect profile. The exact role for ibrutinib in the treatment of MCL is yet to be established; however, it is likely to fundamentally change the way we treat this disease.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Clinical Trials as Topic; Half-Life; Hematologic Diseases; Humans; Immunotherapy; Lymphoma, Mantle-Cell; Middle Aged; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Rituximab; Signal Transduction; Treatment Outcome

Topics: Adult; Female; Hematologic Diseases; Humans; Male; Piperidines; Propiophenones