piperidines and Hematologic-Neoplasms

Greater understanding of the mechanisms involved in the disease progression of haematological malignancies has led to the introduction of novel targeted therapies with reduced toxicity compared with chemotherapy-based regimens, which has expanded the treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a first-in-class Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with CLL/SLL or relapsed/refractory MCL. However, next-generation BTK inhibitors have been developed with improved specificity and the potential to reduce the off-target toxicity observed with ibrutinib. Acalabrutinib is a highly selective, next-generation BTK inhibitor, which was granted accelerated approval by the US Food and Drug Administration in 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. In November 2019, it was also granted approval for the treatment of adult patients with CLL/SLL on the basis of two phase 3 clinical trials. This review describes the current understanding of acalabrutinib according to clinical study data for the treatment of MCL and CLL/SLL and shares recommendations from our practice on how it should be used when treating patients in the clinic, including dosing, administration and management of adverse events.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Benzamides; Clinical Trials as Topic; Disease Progression; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Middle Aged; Piperidines; Practice Patterns, Physicians'; Pyrazines; Safety; Treatment Outcome; United States; United States Food and Drug Administration

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Chemistry, Pharmaceutical; COVID-19 Drug Treatment; Drug Delivery Systems; Hematologic Neoplasms; Humans; Inflammation; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; SARS-CoV-2

Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) in B lymphocytes as well as other kinases including interleukin-2-inducible T-cell kinase (ITK) in CD4+ Th2 regulatory T cells. Increased infections have been observed in patients taking ibrutinib. The overall incidence has not been systematically evaluated.. The published literature and conference abstracts of prospective clinical trials using ibrutinib in hematologic malignancies were identified and reviewed using PubMed, Google Scholar, and HemOnc.org per PRISMA guidelines. Infectious events with a focus on pneumonia were collated per the Common Terminology Criteria for Adverse Events Version 4.03 grading.. Infectious complications are common, occurring in 56% of patients taking single-agent ibrutinib and 52% of those on combination therapy. Approximately one in 5 patients developed pneumonia, which was the major contributor to a 2% rate of death from infections. Many of the cases of pneumonia were due to opportunistic pathogens.. Ibrutinib use requires prudent consideration of the impacts on host immunity. We identified a high rate of serious adverse infectious events within prospective clinical trials. Data suggest a role of both BTK and ITK inhibition for the increased events. There was considerable variability in the reporting of adverse events between trials, journals, and conference reports.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Infections; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

The Bruton tyrosine kinase inhibitor ibrutinib (IB) has attained an important role in the treatment of patients with chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenström macroglobulinemia, significantly improving clinical outcomes. However, IB therapy has been associated with an increased risk of atrial fibrillation (AF) and bleeding. We report on the expert opinion that a group of Italian haematologists, cardiologists, and pharmacologists jointly released to improve the practical management of patients at risk for AF and bleeding during treatment with IB. A proper pretreatment assessment to identify patients who are at a higher risk, careful choice of concomitant drugs, regular monitoring, and multispecialist approach were characterized as the main principles of clinical management of these patients. For patients developing AF, anticoagulant and antiarrhythmic therapy must be guided by considerations about efficacy, safety, and risk of pharmacokinetic interactions with IB. For patients experiencing bleeding or requiring procedures that increase the risk of bleeding, considerations about platelet turnover, IB-related platelet dysfunctions, and bleeding worsening by concomitant anticoagulants or antiplatelet agents provide clues to manage bleeding. Overall, AF and bleeding are manageable clinical events in patients receiving IB, not requiring drug interruption in most cases. Preexisting AF should not represent an absolute contraindication to IB therapy. For each patient candidate for IB, strategies of risk assessment and mitigation may allow to exploit the life-saving effects of in chronic lymphocytic leukaemia and mantle cell lymphoma.

Topics: Adenine; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Hematologic Neoplasms; Hemorrhage; Humans; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk Factors

Hematologic cancers can occur from the overactivity of Bruton's tyrosine kinase, a proto-oncogene in blood cell maturation. Ibrutinib, a new oral targeted therapy drug, is the first agent that binds to the Bruton's tyrosine kinases and inhibits overgrowth of B cells. In blocking this overgrowth, ibrutinib has been shown to achieve lengthy remissions for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Remissions are highly valued in these cancers; cure is rare in MCL, and CLL is incurable.. This article reviews ibrutinib, its risks and benefits, and the role that oncology nurses play in educating patients and promoting drug adherence.. A comprehensive review of the literature was conducted using key words such as ibrutinib, mantle cell lymphoma, chronic lymphocytic leukemia, tyrosine kinase inhibitor, and oral chemotherapy.. Ibrutinib has been shown to be well tolerated, with manageable, low-grade toxicities compared to traditional cytotoxic agents. For all patients with a hematologic cancer, but particularly for the large proportion of older adults affected by hematologic malignancies, ibrutinib provides a new treatment option with a low toxicity profile.

Topics: Adenine; Antineoplastic Agents; Clinical Trials as Topic; Drug Interactions; Hematologic Neoplasms; Humans; Piperidines; Proto-Oncogene Mas; Pyrazoles; Pyrimidines

Topics: Boronic Acids; Bortezomib; Cyclin-Dependent Kinases; Enzyme Inhibitors; Flavonoids; Hematologic Neoplasms; Humans; NF-kappa B; Piperidines; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines

JAK3 is a non-receptor tyrosine kinase, predominantly expressed in hematopoietic cells and that has been implicated in the signal transduction of the common gamma chain subfamily of cytokine receptors. As a result, JAK3 plays an essential role in hematopoieisis during T cell development. JAK3 inactivating mutations result in immunodeficiency syndromes (SCID) in both humans and mice. Recent data indicate that abnormal activation of JAK3 due to activating mutations is also found in human hematological malignancies, including acute megakaryoblastic leukemia (AMKL) and cutaneous T cell lymphoma (CTCL). After a brief summary of the JAK3 structure and function, we will review the evidence on the emerging role of JAK3 activation in hematological malignancies that warrant further studies to test the relevance of specific inhibition of JAK3 as a therapeutic approach to these challenging clinical entities.

Topics: Animals; Gene Expression Regulation, Neoplastic; Hematologic Neoplasms; Humans; Interleukin Receptor Common gamma Subunit; Janus Kinase 3; Lymphocytes; Mice; Piperidines; Pyrimidines; Pyrroles; Receptors, Cytokine; Signal Transduction

Farnesyltransferase inhibitors (FTIs) inhibit certain cellular signal transduction pathways, and are being evaluated for activity in hematologic malignancies. Tipifarnib and lonafarnib are orally available FTIs that are active against a variety of targets and inhibit several pathways involved in the pathogenesis of hematologic malignancies. FTIs have demonstrated activity in a variety of hematologic diseases, including acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, and multiple myeloma. This article reviews the clinical experience with tipifarnib and lonafarnib in the treatment of hematologic malignancies.

Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Hematologic Neoplasms; Humans; Piperidines; Pyridines; Quinolones; Signal Transduction

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematologic malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two nonpeptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy, with overall response rates of 30% and complete remissions in about 15%. Dose-limiting adverse effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated primarily with diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this lack of evidence, significant clinical efficacy of the FTIs has been observed in MDS, on a par with the efficacy of currently available chemotherapeutic agents, leading to further development of this new class of drugs in MDS and AML.

Topics: Adult; Aged; Antineoplastic Agents; Bone Marrow Diseases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Farnesyltranstransferase; Gastrointestinal Diseases; Genes, ras; Hematologic Neoplasms; Humans; Middle Aged; Myelodysplastic Syndromes; Piperidines; Prenylation; Protein Processing, Post-Translational; Pyridines; Quinolones; Treatment Outcome

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematological malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two non-peptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy with overall response rates of 30%, with complete remissions in about 15%. Dose-limiting side effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated with primarily diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this, significant clinical efficacy of the FTIs in MDS, on par with that of currently available chemotherapeutic agents, has been observed, leading to further development of this new class of drugs in MDS and AML.

Topics: Acute Disease; Aged; Alkyl and Aryl Transferases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Hematologic Neoplasms; Humans; Leukemia, Myeloid; Middle Aged; Myelodysplastic Syndromes; Piperidines; Protein Prenylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); Pyridines; Quinolones; Remission Induction; Signal Transduction; Treatment Outcome

Cyclin-dependent kinases (CDKs) have long been known to be the main facilitators of the cell proliferation cycle. However, they also play important roles in the regulation of the RNA polymerase II transcription cycle. Cancer cells display aberrant cell cycle regulation to gain proliferative advantages and they also appear to have an exaggerated dependence on RNA polymerase II transcriptional activity to sustain pro-survival and antiapoptotic signalling. A picture is now starting to emerge that both the cell-cycle and transcriptional functions of CDKs can be exploited pharmacologically with CDK inhibitors that possess appropriate selectivity profiles. In this article, recent advances into these mechanistic insights and how they can guide clinical development in terms of choice of indication are reviewed, as well as combinations with existing chemotherapies. An overview is also given of recent clinical trial results with the lead CDK inhibitor drug candidates seliciclib (CYC202, (R)-roscovitine; Cyclacel) and alvocidib (flavopiridol; Aventis-NCI), as well as the development of other clinical entries and advanced preclinical compounds. The discussion focuses on oncology, but we point out recent results with CDK inhibitors in virology and nephrology.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Clinical Trials as Topic; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Female; Flavonoids; Glomerulonephritis; Hematologic Neoplasms; HIV Infections; Humans; Molecular Sequence Data; Piperidines; Protein Kinase Inhibitors; Purines; Roscovitine; Transcription, Genetic

Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FTase). Initially developed to inhibit the prenylation necessary for Ras activation, their mechanism of action seems to be more complex, involving other proteins unrelated to Ras. FTIs have been developed and tested across a wide range of human cancers. At least 3 agents within this family have been investigated in hematologic malignancies. These are tipifarnib (R115777, Zarnestra), lonafarnib (SCH66336, Sarasar), both of which are orally administered, and BMS-214662, which is given intravenously. Preliminary results from clinical trials demonstrate enzyme target inhibition, a favorable toxicity profile and promising efficacy. Ongoing studies will better determine their mechanism of action and the role of combination with other agents, defining their place in the therapeutic arsenal of hematologic disorders.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Benzodiazepines; Cell Line, Tumor; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Hematologic Neoplasms; Humans; Imidazoles; Piperidines; Pyridines; Quinolones; ras Proteins; Signal Transduction

An increasing number of unique active new chemotherapeutic and biologic agents are currently available for clinical research studies. Nucleoside analogs in development for non-Hodgkin's lymphoma (NHL) include clofarabine, troxacitabine, and bendamustine, a hybrid of an alkylating nitrogen mustard group and a purine-like benzimidazole, with demonstrated activity in NHL. Drugs directed at the cell cycle include flavopiridol and UCN-01. The proteasome plays a pivotal role in cellular protein regulation and activation of NFkappaB, which maintains cell viability through the transcription of inhibitors of apoptosis. PS-341 is a specific, selective inhibitor of the 26S proteasome which induces apoptosis and has activity in cell types characterized by overexpression of Bcl-2. Response rates of 50%, including complete remissions, have been reported using this agent in patients with refractory multiple myeloma. Studies are ongoing in NHL and chronic lymphocytic leukemia. G3139, an antisense oligonucleotide, has shown promise in early studies. Rituximab has revolutionized the treatment of NHL. However, other active antibodies are now available, including alemtuzumab, epratuzumab, and Hu1D10. The radioimmunoconjugates (90)Y-ibritumomab tiuxetan and (131)I-tositumomab may also play an important role in the management of NHL. Future therapeutic strategies should involve rational combinations of new chemotherapy drugs, biologic agents, and antisense compounds to increase the cure rate in patients with lymphoma.

Topics: Adenine Nucleotides; Alemtuzumab; Alkaloids; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Agents; Apoptosis; Arabinonucleosides; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Cell Cycle; Cell Survival; Clofarabine; Cytosine; Dioxolanes; Flavonoids; Hematologic Neoplasms; Humans; Immunoconjugates; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoma, Non-Hodgkin; Multiple Myeloma; NF-kappa B; Nitrogen Mustard Compounds; Oligonucleotides, Antisense; Peptide Hydrolases; Piperidines; Protease Inhibitors; Proteasome Endopeptidase Complex; Pyrazines; Remission Induction; Rituximab; Staurosporine; Thionucleotides

The majority of hematopoietic malignancies have aberrancies in the retinoblastoma (Rb) pathway. Loss in Rb function is, in most cases, a result of the phosphorylation and inactivation of Rb by the cyclin-dependent kinases (cdks), main regulators of cell cycle progression. Flavopiridol, the first cdk modulator tested in clinical trials, is a flavonoid that inhibits several cdks with evidence of cell cycle block. Other interesting preclinical features are the induction of apoptosis, promotion of differentiation, inhibition of angiogenic processes and modulation of transcriptional events. Initial clinical trials with infusional flavopiridol demonstrated activity in some patients with non-Hodgkin's lymphoma, renal, prostate, colon and gastric carcinomas. Main side-effects were secretory diarrhea and a pro-inflammatory syndrome associated with hypotension. Phase 2 trials with infusional flavopiridol in CLL and mantle cell lymphoma, other schedules and combination with standard chemotherapies are ongoing. The second cdk modulator tested in clinical trials, UCN-01, is a potent protein kinase C inhibitor that inhibits cdk activity in vitro as well. UCN-01 blocks cell cycle progression and promotes apoptosis in hematopoietic models. Moreover, UCN-01 is able to abrogate checkpoints induced by genotoxic stress due to modulation in chk1 kinase. The first clinical trial of UCN-01 demonstrated very prolonged half-life (approximately 600 h), 100 times longer than the half-life observed in preclinical models. This effect is due to high binding affinity of UCN-01 to the human plasma protein alpha-1-acid glycoprotein. Main side-effects in this trial were headaches, nausea/vomiting, hypoxemia and hyperglycemia. Clinical activity was observed in patients with melanoma, non-Hodgkin's lymphoma and leiomyosarcoma. Of interest, a patient with anaplastic large cell lymphoma refractory to high-dose chemotherapy showed no evidence of disease after 3 years of UCN-01 therapy. Trials of infusional UCN-01 in combination with Ara-C or gemcitabine in patients with acute leukemia and CLL, respectively, have commenced. In conclusion, flavopiridol and UCN-01 are cdk modulators that reach biologically active concentrations effective in modulating CDK in vitro, and show encouraging results in early clinical trials in patients with refractory hematopoietic malignancies. Although important questions remain to be answered, these positive experiences will hopefully increase the therapeutic modali

Topics: Alkaloids; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinases; Enzyme Inhibitors; Flavonoids; Hematologic Neoplasms; Humans; Piperidines; Retinoblastoma Protein; Signal Transduction; Staurosporine

Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.

Topics: Adenine; Aged; Antihypertensive Agents; Female; Heart Diseases; Hematologic Neoplasms; Humans; Hypertension; Incidence; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Stroke

Ibrutinib increases the risk of atrial fibrillation (AF) and is associated with bleeding tendencies. Reported rates of arrhythmia are variable in different studies. The aim of the current analysis was to evaluate the incidence of AF in a single-center cohort of patients.. This analysis was conducted at Hunter New England Local Health District, Australia between April 1, 2015 and June 30, 2017. We included all consecutive patients commenced on ibrutinib for hematological malignancies. Patients with a history of paroxysmal AF were excluded. The primary end point was incidence of AF. Time to diagnosis and management were secondary outcomes of interest.. A total of 24 patients (age 73 ± 9 years, males n = 16 [67%]) were commenced on ibrutinib treatment during the study period with chronic lymphocytic leukemia (n = 21, 88%) as the main indication. During a median follow-up of 12 months, four (17%) patients were diagnosed with AF with increasing age, duration of ibrutinib treatment as associations. The median time to AF diagnosis was 9 (interquartile range [IQR]: 7-18) months. All patients were managed with a rate control strategy with beta blockers as the preferred agents. Three (75%) patients were commenced on anticoagulation for stroke prevention. During a follow-up of 18 (IQR: 17-23) months following AF onset, one patient required hospitalization for AF. There were no bleeding complications reported.. In conclusion, this series noted a higher incidence of AF than previously reported. Oncologists and cardiologists need to be aware of the increased risk of AF in patients receiving ibrutinib.

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Australia; Female; Hematologic Neoplasms; Hospitalization; Humans; Incidence; Male; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Survival Rate

PHEDRA (Platform for Haematology in EMEA: Data for Real World Analysis) is a unique, noninterventional project based on secondary data collection from real-world (RW) patient-level (health record) databases to understand treatment patterns in hematological malignancies. It compares ibrutinib's effectiveness with alternative treatments using RW data (RWD) and randomized clinical trials data.. RWD are cleaned, validated, harmonized into a Common Data Model, and analyzed statistically alongside randomized clinical trial data. Treatment outcomes include overall and progression-free survival.. To date, RWD (four databases) are available for 2840 patients in three indications, collected between 1990 and 2017.. PHEDRA is an innovative approach to generate evidence to inform optimal treatment decisions in RW settings.

Topics: Adenine; Comparative Effectiveness Research; Data Collection; Databases, Factual; Hematologic Neoplasms; Humans; Longitudinal Studies; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies; Treatment Outcome

Topics: Adenine; Aged; Aged, 80 and over; Female; Follow-Up Studies; Hematologic Neoplasms; Hepatitis B; Hepatitis B virus; Humans; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Virus Activation

This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1-4 and 14-18), and ibrutinib 140 mg (Days 5-13; 19-27) plus erythromycin 500 mg tid (Days 5-11) and voriconazole 200 mg bid (Days 19-25). Twenty-six patients (median [range] age: 64.5 [50-88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97-103.51) and 143.3 (107.77-190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.

Topics: Adenine; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Erythromycin; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Neutropenia; Piperidines; Polymorphism, Single Nucleotide; Pyrazoles; Pyrimidines; Voriconazole

Patients with refractory or relapsed haematological malignancies have few treatment options and short survival times. Identification of effective therapies with genomic-based precision medicine is hampered by intratumour heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Ex-vivo drug-response profiling in patient biopsies might aid effective treatment identification; however, proof of its clinical utility is limited.. We investigated the feasibility and clinical impact of multiparametric, single-cell, drug-response profiling in patient biopsies by immunofluorescence, automated microscopy, and image analysis, an approach we call pharmacoscopy. First, the ability of pharmacoscopy to separate responders from non-responders was evaluated retrospectively for a cohort of 20 newly diagnosed and previously untreated patients with acute myeloid leukaemia. Next, 48 patients with aggressive haematological malignancies were prospectively evaluated for pharmacoscopy-guided treatment, of whom 17 could receive the treatment. The primary endpoint was progression-free survival in pharmacoscopy-treated patients, as compared with their own progression-free survival for the most recent regimen on which they had progressive disease. This trial is ongoing and registered with ClinicalTrials.gov, number NCT03096821.. Pharmacoscopy retrospectively predicted the clinical response of 20 acute myeloid leukaemia patients to initial therapy with 88·1% accuracy. In this interim analysis, 15 (88%) of 17 patients receiving pharmacoscopy-guided treatment had an overall response compared with four (24%) of 17 patients with their most recent regimen (odds ratio 24·38 [95% CI 3·99-125·4], p=0·0013). 12 (71%) of 17 patients had a progression-free survival ratio of 1·3 or higher, and median progression-free survival increased by four times, from 5·7 (95% CI 4·1-12·1) weeks to 22·6 (7·4-34·0) weeks (hazard ratio 3·14 [95% CI 1·37-7·22], p=0·0075).. Routine clinical integration of pharmacoscopy for treatment selection is technically feasible, and led to improved treatment of patients with aggressive refractory haematological malignancies in an initial patient cohort, warranting further investigation.. Austrian Academy of Sciences; European Research Council; Austrian Science Fund; Austrian Federal Ministry of Science, Research and Economy; National Foundation for Research, Technology and Development; Anniversary Fund of the Austrian National Bank; MPN Research Foundation; European Molecular Biology Organization; and Swiss National Science Foundation.

Topics: Adenine; Adult; Aged; Antineoplastic Agents; Area Under Curve; Bone Marrow; Bortezomib; Cladribine; Disease-Free Survival; Female; Hematologic Neoplasms; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Microscopy, Fluorescence; Middle Aged; Odds Ratio; Pilot Projects; Piperidines; Positron Emission Tomography Computed Tomography; Pyrazoles; Pyrimidines; Remission Induction; ROC Curve; Young Adult

Short hemato-oncologic procedures are often painful in children, and sedation should be performed outside the operating room.. : The study aims to compare the effects of remifentanil with those of fentanyl administered during short hemato-oncologic interventions in children.. A prospective, randomized study was planned for 29 ASA I to III children (aged, 2 to 18 y) to undergo a total of 60 short oncologic interventions. The patients were placed into 2 groups: propofol-remifentanil (group PR) and propofol-fentanyl (group PF). Group PR was first administered propofol (2 mg/kg) and then remifentanil bolus (0.5 μg/kg). Group PF was first administered propofol (2 mg/kg) and then fentanyl bolus (0.5 μg/kg). Systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, respiratory rate, peripheral oxygen saturation, and heart rate were recorded every 3 minutes during the intervention and every 5 minutes after the operation. Postanesthetic recovery scores, eye-opening time to speech, and recovery time were recorded.. Comparison of diastolic arterial pressure in groups at minute 3 of the procedure showed significant difference (P<0.05). Eye-opening to speech (P=0.043) and recovery times (P=0.002) were shorter in group PR.. During short hemato-oncologic interventions in children, the PR combination is a suitable one for early recovery.

Topics: Adolescent; Analgesics, Opioid; Blood Pressure; Child; Child, Preschool; Conscious Sedation; Female; Fentanyl; Heart Rate; Hematologic Neoplasms; Humans; Hypnotics and Sedatives; Male; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiration

This prospective randomized study was designed to evaluate the effects of adding remifentanil to the standard propofol-based technique in the setting of paediatric haematology-oncology outpatient clinic.. Eighty ASA III paediatric patients treated in the outpatient haematology-oncology clinic requiring bone marrow aspiration were randomly assigned either to the propofol (P) or the propofol/remifentanil (PR) group. The quality of anaesthesia and recovery were evaluated.. The total amount of propofol required to prevent patient movement was lower in the PR group. The time interval to eye opening and to home readiness was significantly lower in the PR group. Adverse respiratory events (RR < 10.min-1 or SpO2 < 90%) occurred significantly more in the propofol/remifentanil group.. The addition of remifentanil improved the conditions during the procedure and reduced the total amount of propofol, as well as the time to home readiness. However, the addition of remifentanil is associated with an increased risk of respiratory depression.

Topics: Adolescent; Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Intravenous; Biopsy, Needle; Bone Marrow; Child; Female; Hematologic Neoplasms; Hemodynamics; Humans; Male; Neoplasms; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiratory Mechanics

Since the broad implementation of ibrutinib therapy, an increasing number of studies have been reported on invasive fungal infections (IFI) associated with ibrutinib administration. We conducted a retrospective cohort study in three hospitals in south-east Austria in order to assess the local epidemiology of ibrutinib associated IFIs. A total of 113 patients with underlying hematological malignancy were included in the study. During the study period, a single IFI episode was observed, which corresponds to an IFI incidence of 2.3 cases per 100 person years (95% CI: 0.12-11.47). IFIs during ibrutinib therapy seem to be a rare event in case of absent additional risk factors for IFIs.. Ibrutinib is an effective drug used to treat a variety of blood cancers, but it might increase risk for life-threatening invasive fungal infections (IFIs). In our study, a low number (1 IFI per 43 patient years) of patients on ibrutinib developed an IFI.

Topics: Adenine; Animals; Antifungal Agents; Austria; Hematologic Neoplasms; Humans; Incidence; Invasive Fungal Infections; Piperidines; Retrospective Studies

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA-sequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the down-regulated gene list. Furthermore, In vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC-1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P = 0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease.

Topics: Adenine; Animals; Apoptosis; Benzodiazepines; Bortezomib; Hematologic Neoplasms; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Mice, Inbred NOD; Mice, SCID; NF-kappa B; Piperidines; Pyrroles; Tumor Microenvironment

Topics: Adenine; Aniline Compounds; COVID-19 Drug Treatment; Drug Repositioning; Hematologic Neoplasms; Humans; Imatinib Mesylate; Janus Kinases; Nitriles; Oligopeptides; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Quinolines

Ibrutinib is a novel drug used in haematological malignancies. Its use is associated with an increased risk of atrial fibrillation (AF), which, in turn, exposes patients to embolic risk, including stroke. Reducing this risk requires anticoagulant therapy which is a matter of concern in the context of the increased bleeding risk of patients with haematological malignancies. In this context the presence of thrombocytopenia related to haematological disorder, ibrutinib-anticoagulants and ibrutinib-platelets interactions contribute to the amplification of the problem. The correct assessment of the thrombosis vs. haemorrhage balance represents a significant challenge for the clinician. In this paper we discuss practical issues related to anticoagulation in patients treated with ibrutinib and incident AF.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Hematologic Neoplasms; Hemorrhage; Humans; Piperidines; Risk Factors; Stroke; Thromboembolism

Topics: Adenine; Betacoronavirus; Checklist; Coronavirus Infections; COVID-19; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pandemics; Piperidines; Pneumonia, Viral; Prescriptions; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; SARS-CoV-2; Surveys and Questionnaires; Telemedicine; Time-to-Treatment

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell development, differentiation and B-cell receptor (BCR) signaling. The use of Bruton's tyrosine kinase inhibitors (BTKi) in the treatment of lymphoid malignancies has dramatically increased, owing to both impressive efficacy and ease of administration. However, BTKi have a range of drug-drug and drug-food interactions, which may alter drug efficacy and/or increase toxicity. Healthcare professionals should be aware of the probability of drug interactions with BTKi and make recommendations accordingly. In this article, we discuss the relevant drug-drug and drug-food interactions associated with ibrutinib, acalabrutinib, and zanubrutinib, and provide clinical practice recommendations for managing these interactions based on the available literature.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Citrus paradisi; Citrus sinensis; Comorbidity; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inducers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Food-Drug Interactions; Fruit and Vegetable Juices; Hematologic Neoplasms; Humans; Lymphoproliferative Disorders; Piperidines; Polypharmacy; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Signal Transduction

Topics: Adenine; Adult; Aged; Aged, 80 and over; Hematologic Neoplasms; Hemorrhage; Humans; Incidence; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors; Thrombosis

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Piperidines; Progression-Free Survival; Pyrazoles; Pyrimidines; Rituximab

Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.

Topics: Adenine; Aged; Female; Hematologic Neoplasms; Hemorrhage; Humans; Incidence; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk Factors; Time Factors

Mutations in two type-3 receptor tyrosine kinases (RTKs), KIT and FLT3, are common in both acute myeloid leukaemia (AML) and systemic mastocytosis (SM) and lead to hyperactivation of key signalling pathways. A large number of tyrosine kinase inhibitors (TKIs) have been developed that target either FLT3 or KIT and significant clinical benefit has been demonstrated in multiple clinical trials. Given the structural similarity of FLT3 and KIT, it is not surprising that some of these TKIs inhibit both of these receptors. This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KIT D816V-positive SM. Here, we compare the in vitro activities of the clinically available FLT3 and KIT inhibitors with those of midostaurin against a panel of cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild-type (wt) FLT3, FLT3-internal tandem duplication (ITD), FLT3 D835Y, the resistance mutant FLT3-ITD+ F691L, KIT D816V, and KIT N822K. We also examined the effects of these inhibitors in vitro and in vivo on cells expressing mutations in c-CBL found in AML that result in hypersensitization of RTKs, such as FLT3 and KIT. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Cell Line, Tumor; Drug Screening Assays, Antitumor; fms-Like Tyrosine Kinase 3; Hematologic Neoplasms; Humans; Mutant Proteins; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-cbl; Proto-Oncogene Proteins c-kit; Pyrazines; Pyrazoles; Pyrroles; Sorafenib; Staurosporine; Triazines

Matrix high-throughput screening (HTS) methods are increasingly employed to rapidly define potential therapeutic drug combinations. We used combination HTS to identify compounds showing synergistic anti-proliferative activity with ibrutinib, an irreversible, small-molecule inhibitor of Bruton's tyrosine kinase. The goal was to identify ibrutinib combinations with maximum synergistic effects in heme malignancy lines, particularly in non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). Growth inhibition (GI) was used to measure cell viability; synergy scores characterized strength of synergistic interaction. Single-agent ibrutinib demonstrated varying degrees of activity across 30 cell lines evaluated. In DLBCL lines, TMD8 was the most sensitive to ibrutinib (GI

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Hematologic Neoplasms; High-Throughput Screening Assays; Humans; Lymphoma, Non-Hodgkin; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction

Opportunistic infections caused by Pneumocystis jirovecii, Cryptococcus neoformans, and ubiquitous airborne filamentous fungi have been recently reported in patients with hematological cancers historically considered at low risk for invasive fungal infections (IFIs), after receipt of the Bruton tyrosine kinase inhibitor ibrutinib. The spectrum and severity of IFIs often observed in these patients implies the presence of a complex immunodeficiency that may not be solely attributed to mere inhibition of Bruton tyrosine kinase. In view of the surge in development of small molecule kinase inhibitors for treatment of malignant and autoimmune diseases, it is possible that there would be an emergence of IFIs associated with the effects of these molecules on the immune system. Preclinical assessment of the immunosuppressive effects of kinase inhibitors and human studies aimed at improving patient risk stratification for development of IFIs could lead to prevention, earlier diagnosis, and better outcomes in affected patients.

Topics: Adenine; Aged; Aged, 80 and over; Female; Fungi; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Invasive Fungal Infections; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction

Topics: Adenine; Child; Costs and Cost Analysis; Hematologic Neoplasms; Humans; Imatinib Mesylate; Piperidines; Pyrazoles; Pyrimidines; Quality of Life; Young Adult

The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater.. A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications.. We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01).. The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Follow-Up Studies; Hematologic Neoplasms; Hemorrhage; Humans; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors; Survival Rate

The effect of the plant-derived vanilloid, capsaicin (CAP), on the metabolic activity of THP-1, U266B1 and U937 hematological malignancy cells was determined. CAP reduced metabolic activity in a concentration-dependent manner in the three cell lines. A biphasic effect was observed on THP-1 cells (EC50: IC50 (95% CI) 32.9 (19.9-54.3)/219 (144-246) µmol/l). U266B1 cells were more resistant to CAP than THP-1 and U937. Metabolic activity was significantly inhibited by CAP in U937 compared to U266B1 cells (IC50: 197 versus 431 µmol/l, respectively, p < 0.008). Transient receptor potential vanilloid-1 (TRPV1) and CB1 antagonists (SB452533 and AM251, respectively) suppressed the CAP-induced increase in THP-1 cell metabolic activity (p < 0.001). AM251 and SB452533 appeared to act as partial agonists and displayed a synergistic effect with CAP in U937 cells. CAP inhibits the metabolic activity of malignant hematological cells through non-TRPV1-dependent mechanisms.

Topics: Cannabinoid Receptor Antagonists; Capsaicin; Cell Death; Cell Line, Tumor; Hematologic Neoplasms; Humans; Indoles; Oxazines; Piperidines; Pyrazoles; TRPV Cation Channels; Xanthenes

Ibrutinib is a covalent and irreversible inhibitor of Bruton's tyrosine kinase (BTK) and has been approved for the treatment of haematological malignancies, such as chronic lymphocytic leukaemia, mantle cell lymphoma and Waldenström's macroglobulinemia. The covalent and irreversible nature of its molecular mode of action allows identification and monitoring of its target in an activity-based protein profiling (ABPP) setting. Fluorescent and biotinylated ibrutinib derivatives have appeared in the literature in recent years to monitor BTK in vitro and in situ. The work described here complements this existing methodology and pertains a comparative study on the efficacy of direct and two-step bioorthogonal ABPP of BTK.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Hematologic Neoplasms; Humans; Molecular Probes; Netherlands; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Topics: Adenine; Antineoplastic Agents; Casein Kinase II; Drug Synergism; Hematologic Neoplasms; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Naphthyridines; Phenazines; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; Vidarabine

APO866 inhibits nicotinamide phosphoribosyltransferase (NMPRTase), a key enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis from the natural precursor nicotinamide. Intracellular NAD is essential for cell survival, and NAD depletion resulting from APO866 treatment elicits tumor cell death. Here, we determine the in vitro and in vivo sensitivities of hematologic cancer cells to APO866 using a panel of cell lines (n = 45) and primary cells (n = 32). Most cancer cells (acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], mantle cell lymphoma [MCL], chronic lymphocytic leukemia [CLL], and T-cell lymphoma), but not normal hematopoietic progenitor cells, were sensitive to low concentrations of APO866 as measured in cytotoxicity and clonogenic assays. Treatment with APO866 decreased intracellular NAD and adenosine triphosphate (ATP) at 24 hours and 48 to72 hours, respectively. The NAD depletion led to cell death. At 96 hours, APO866-mediated cell death occurred in a caspase-independent mode, and was associated with mitochondrial dysfunction and autophagy. Further, in vivo administration of APO866 as a single agent prevented and abrogated tumor growth in animal models of human AML, lymphoblastic lymphoma, and leukemia without significant toxicity to the animals. The results support the potential of APO866 for treating hematologic malignancies.

Topics: Acrylamides; Animals; Antineoplastic Agents; Cell Death; Cytokines; Dose-Response Relationship, Drug; Hematologic Neoplasms; HL-60 Cells; Humans; Jurkat Cells; K562 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Tumor Cells, Cultured; U937 Cells; Xenograft Model Antitumor Assays

Topics: Acrylamides; Apoptosis; Drug Evaluation, Preclinical; Hematologic Neoplasms; Humans; Piperidines