piperidines and Tumor-Lysis-Syndrome

Background Tumor lysis syndrome results when intracellular contents are released during cell lysis. Ibrutinib, a Bruton tyrosine kinase inhibitor, is used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Tumor lysis syndrome caused by ibrutinib therapy is potentially life threatening, but is rare and not often reported in clinical trials. Objective The purpose of this case series is to describe the occurrence of tumor lysis syndrome in two patients initiated on ibrutinib, and to highlight the importance of close monitoring during therapy. Discussion One patient with chronic lymphocytic leukemia/small lymphocytic lymphoma and one patient with mantle cell lymphoma developed laboratory and clinical tumor lysis syndrome following initiation of ibrutinib therapy. Assessment with the Naranjo Adverse Drug Reaction Probability Scale indicated one probable relationship and one possible relationship between ibrutinib therapy and tumor lysis syndrome. There were additional factors that may have confounded the laboratory and clinical factors observed, including baseline laboratory values and concurrent medications. Both patients were managed with supportive therapies. A literature review identified five additional reported cases of tumor lysis syndrome following ibrutinib therapy. Conclusion This case series identifies one patient with a probable relationship and one patient with a possible relationship between the development of tumor lysis syndrome and treatment with ibrutinib. Although uncommon, proper attention should be given to monitoring for this adverse drug reaction and appropriate follow-up should occur despite ibrutinib's ease of administration.

Topics: Adenine; Aged; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tumor Lysis Syndrome

There have been minimal therapeutic advancements in acute myeloid leukemia (AML) over the past 4 decades and outcomes remain unsatisfactory. Alvocidib (formerly flavopiridol) is a multi-serine threonine cyclin-dependent kinase inhibitor with demonstrable in vitro and clinical activity in AML when combined in a timed sequential chemotherapy regimen, FLAM (alvocidib followed by cytarabine continuous infusion and mitoxantrone). FLAM has been evaluated in sequential phase 1 and phase 2 studies in 149 and 256 relapsed/refractory and newly diagnosed non-favorable risk AML patients, respectively, with encouraging findings in both patient populations warranting further investigation. This review highlights the mechanism of action of alvocidib, pre-clinical studies of alvocidib in AML, and the clinical trials evaluating alvocidib alone and in combination with cytotoxic agents (FLAM) in AML.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Cycle; Cyclin-Dependent Kinases; Drug Interactions; Drug Screening Assays, Antitumor; Flavonoids; Humans; Leukemia, Myeloid, Acute; Molecular Structure; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Piperidines; Protein Kinase Inhibitors; Salvage Therapy; Tumor Lysis Syndrome

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

Flavopiridol and lenalidomide have activity in refractory CLL without immunosuppression or opportunistic infections seen with other therapies. We hypothesized that flavopiridol treatment could adequately de-bulk disease prior to lenalidomide therapy, decreasing the incidence of tumor flare with higher doses of lenalidomide. In this Phase I study, the maximum tolerated dose was not reached with treatment consisting of flavopiridol 30 mg m(-2) intravenous bolus (IVB) + 30 mg m(-2) continuous intravenous infusion (CIVI) cycle (C) 1 day (D) 1 and 30 mg m(-2) IVB + 50 mg m(-2) CIVI C1 D8,15 and C2-8 D3,10,17 with lenalidomide 15 mg orally daily C2-8 D1-21. There was no unexpected toxicity seen, including no increased tumor lysis, tumor flare (even at higher doses of lenalidomide) or opportunistic infection. Significant clinical activity was demonstrated, with a 51% response rate in this group of heavily pretreated patients. Biomarker testing confirmed association of mitochondrial priming of the BH3 only peptide Puma with response.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Flavonoids; Humans; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Maximum Tolerated Dose; Middle Aged; Piperidines; Recurrence; Thalidomide; Treatment Outcome; Tumor Lysis Syndrome

Flavopiridol, the first clinically evaluated cyclin-dependent kinase inhibitor, shows activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS.. A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early-phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates.. Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy less than 10 cm or 10 cm or more during the first 2 treatments was 0.111 (SE% 13.0%) and 0.265 (SE% 17.9%), respectively, when flavo-G area under the plasma concentration versus time curve was at its median value in whole-patient group.. This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine whether the associations between TLS, gender, and glucuronide metabolites are relevant in patients with chronic lymphocytic leukemia treated with other cyclin-dependent kinase inhibitors.

Topics: Antineoplastic Agents; Female; Flavonoids; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Maximum Tolerated Dose; Models, Biological; Neoplasm Recurrence, Local; Piperidines; Prevalence; Prognosis; Tissue Distribution; Tumor Lysis Syndrome; United States

Flavopiridol, a cyclin-dependent kinase inhibitor, is cytotoxic to leukemic blasts. In a Phase II study, flavopiridol 50 mg/m(2) was given by 1-h infusion daily x 3 beginning day 1 followed by 2 g/m(2)/72 h ara-C beginning day 6 and 40 mg/m(2) mitoxantrone on day 9 (FLAM) to 45 adults with newly diagnosed acute myelogenous leukemia (AML) with multiple poor-risk features. Thirty patients (67%) achieved complete remission (CR) and 4 (9%) died. Twelve (40%) received myeloablative allogeneic bone marrow transplant (BMT) in first CR. Median OS and DFS are not reached (67% alive 12.5-31 months, 58% in CR 11.4-30 months), with median follow-up 22 months. Sixteen received FLAM in CR, with median OS and DFS 9 and 13.1 months, and 36% alive at 21-31 months. Short OS and DFS correlated with adverse cytogenetics, regardless of age or treatment in CR. The addition of allogeneic BMT in CR translates into long OS and DFS in the majority of eligible patients.

Topics: Adult; Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Female; Flavonoids; Follow-Up Studies; Heart Diseases; Humans; Hyperkalemia; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Piperidines; Polyamines; Premedication; Remission Induction; Risk; Sepsis; Sevelamer; Transplantation, Homologous; Treatment Outcome; Tumor Lysis Syndrome; Young Adult

We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Cell Cycle; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Flavonoids; Humans; Inactivation, Metabolic; Infusions, Intravenous; Injections, Intravenous; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Models, Biological; Piperidines; Protein Kinase Inhibitors; Recurrence; Salvage Therapy; Treatment Outcome; Tumor Lysis Syndrome; Uridine Diphosphate Glucuronic Acid; Vidarabine

Patients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.. Patients with relapsed CLL were treated with single-agent flavopiridol, with subsequent addition of dexamethasone to suppress cytokine release syndrome (CRS). High-risk genomic features were prospectively assessed for response to therapy.. Sixty-four patients were enrolled. Median age was 60 years, median number of prior therapies was four, and all patients had received prior purine analog therapy. If patients tolerated treatment during week 1, dose escalation occurred during week 2. Dose escalation did not occur in four patients, as a result of severe tumor lysis syndrome; three of these patients required hemodialysis. Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups. Reducing the number of weekly treatments per cycle from four to three and adding prophylactic dexamethasone, which abrogated interleukin-6 release and CRS (P < or = .01), resulted in improved tolerability and treatment delivery.. Flavopiridol achieves significant clinical activity in patients with relapsed CLL, including those with high-risk genomic features and bulky lymphadenopathy. Subsequent clinical trials should use the amended treatment schedule developed herein and prophylactic corticosteroids.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 17; Dexamethasone; Disease-Free Survival; Female; Flavonoids; Gene Expression Regulation, Leukemic; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Logistic Models; Male; Middle Aged; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Recurrence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Tumor Lysis Syndrome

The phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts.. In both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day).. In the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance <80 mL/minute) from 43% to 18%. Laboratory TLS per Howard criteria occurred in one patient; no clinical TLS was observed.. Three cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Creatinine; Cytoreduction Surgical Procedures; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Piperidines; Sulfonamides; Tumor Lysis Syndrome

Tumor lysis syndrome is an oncologic emergency resulting from rapid and massive tumor cell death that may lead to serious clinical complications including acute kidney injury and cardiac arrest. Tumor lysis syndrome most often occurs after the initiation of cytotoxic therapy in patients with high-grade lymphomas and acute lymphoblastic leukemia.. We present a first case of patient with chemotherapy-resistant chronic lymphocytic leukemia and small lymphocytic lymphoma who developed tumor lysis syndrome upon treatment with ibrutinib (Imbruvica), a novel tyrosine kinase inhibitor.. The patient showed dramatic improvement in kidney function, uric acid and phosphorus after discontinuation of ibrutinib and a short course of rasburicase (recombinant urate oxidase), and two haemodialysis treatments.. Clinicians should be aware of this serious side effect and closely monitor kidney function in patients treated with this oral kinase inhibitor.

Topics: Adenine; Aged; Humans; Kidney; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors; Tumor Lysis Syndrome; Urate Oxidase

Topics: Adenine; Aged; Antineoplastic Agents; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Tumor Burden; Tumor Lysis Syndrome

Mantle cell lymphoma accounts for 5-7% of all non-Hodgkin's lymphomas. Under the current WHO classification, it is categorized as an indolent B cell lymphoma, but has an aggressive clinical course. New insights into leukemogenic molecular pathways of mantle cell lymphoma have uncovered unique therapeutic targets. Ibrutinib, a Bruton's tyrosine kinase inhibitor, is the newest drug in the arsenal that has shown promising efficacy in relapsed mantle cell lymphoma. Long-term studies have shown that grade 3 or 4 adverse events are infrequent. Asymptomatic lymphocytosis is frequently seen with ibrutinib use in mantle cell lymphoma; however, tumor lysis syndrome is an extremely rare complication. To date, only two patients with ibrutinib-associated tumor lysis syndrome in mantle cell lymphoma have been described in a long-term follow-up study. Both patients met laboratory criteria for tumor lysis syndrome, however, but did not develop clinical tumor lysis syndrome. We, here describe a patient with relapsed mantle cell lymphoma who developed clinical tumor lysis syndrome with ibrutinib monotherapy.

Topics: Adenine; Aged; Antineoplastic Agents; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tumor Lysis Syndrome

Topics: Adenine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) has been described in over 40% of patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. We conducted a retrospective analysis to determine predictive factors for TLS. In 116 patients, the incidence of TLS was 46% (95% CI: 36-55%). In univariable analysis, female gender, greater number of prior therapies, Rai stages III-IV, adenopathy ≥ 10 cm, splenomegaly, del(11q), decreased albumin and increased absolute lymphocyte count, white blood cell count (WBC), β2-microglobulin, and lactate dehydrogenase were associated (P < 0.05) with TLS. In multivariable analysis, female gender, adenopathy ≥ 10 cm, elevated WBC, increased β2-microglobulin, and decreased albumin were associated with TLS (P < 0.05). With respect to patient outcomes, 49 and 44% of patients with and without TLS, respectively, responded to flavopiridol (P = 0.71). In a multivariable analysis, controlling for number of prior therapies, cytogenetics, Rai stage, age and gender, progression-free survival (PFS) was inferior in patients with TLS (P = 0.01). Female patients and patients with elevated β2-microglobulin, increased WBC, adenopathy ≥ 10 cm and decreased albumin were at highest risk and should be monitored for TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclin-Dependent Kinases; Female; Flavonoids; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Piperidines; Retrospective Studies; Risk Factors; Survival Rate; Tissue Distribution; Treatment Outcome; Tumor Lysis Syndrome

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Cytarabine; Drug Administration Schedule; Flavonoids; Follow-Up Studies; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mitoxantrone; Piperidines; Risk; Treatment Outcome; Tumor Lysis Syndrome