Invasive Mycoses in High-Risk Cancer Patients - a Prospective Analysis of Clinical Parameters, Side Effects, Drug Interactions and Costs for the Safe and Economically Appropriate Use of Systemic Antifungal Agents.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2487-2487
Author(s):  
Werner Neubauer ◽  
Alf Zerweck ◽  
Alexandra Goebel ◽  
Beate Lubrich ◽  
Hartmut Bertz ◽  
...  
Keyword(s):  
Side Effects ◽  
High Risk ◽  
Drug Interactions ◽  
Safety Profile ◽  
Research Funding ◽  
Empirical Therapy ◽  
Preemptive Therapy ◽  
Appropriate Use ◽  
Line Therapy ◽  
Invasive Mycoses

Abstract Abstract 2487 Poster Board II-464 Introduction: Invasive mycoses (IM) show high morbidity and mortality rates among immunocompromised patients (pts). Especially allogeneic stem cell transplant (allo-SCT) recipients and acute leukemia pts under induction chemotherapy are at risk and benefit from early systemic antifungal drug (SAD) interventions. Nevertheless, the increasing use of SADs has led to considerable costs and represents a substantial burden for public health systems. Available SADs differ in their antifungal properties, side effects (SE), potential drug interactions (PDI) and costs. Efficacy and safety profiles of SAD have been derived from clinical trials, which, however, may not reflect ‘everyday clinics' and true SAD efficacy due to tight inclusion and exclusion study criteria. Aim of our analysis was to prevent SAD application errors and to assure their economically appropriate use. Methods: Since 11/06, we prospectively analysed the SAD usage on a general hematology ward (n=42) and SCT-unit (n=158) within our department. Pt characteristics, organ function, SE, PDI, treatment outcome and costs were assessed. Data was obtained by daily participation on ward rounds, consultation of ward physicians and review of pts' medication charts. SAD were given according to EORTC-adapted guidelines, with fluconazole given as primary prophylaxis in allo-SCT recipients and posaconazole for AML/MDS pts under induction chemotherapy. Empirical therapy was implemented with liposomal amphotericin B (lip. AmphoB) or caspofungin, preemptive therapy and therapy of aspergillus infections with voriconazole, caspofungin or lip. AmphoB. Results: 200 consecutive pts under SAD treatment showed pt characteristics as displayed in Table 1, with leukemia (n=125) and lymphoma (n=51) as predominant diseases. Transplant (especially allo-SCT) pts were treated more frequently with intravenous (iv) SAD and with two or more consecutively applied SAD. Allo-SCT recipients received SAD earlier with higher pt numbers being treated prophylactically and empirically. The mortality rate due to fungal infections was significantly higher in allo-SCT recipients compared to other subgroups. The median duration of SAD use was considerably longer and median SAD costs exceeded those of auto-SCT and non-transplant pts (Table 1). Lip. AmphoB was primarily applied as empirical therapy and showed an unfavorable safety profile with more SE (predominantly nephrotoxicity) and PDI compared to other SAD (Table 2). Voriconazole (mainly applied as preemptive therapy) and posaconazole displayed hepatotoxicity and numerous pharmacokinetic PDI, whereas caspofungin showed a favorable safety profile, with least SE and PDI. The echinocandin was primarily applied as 2-line therapy, whereas all other SAD were commonly given as 1-line therapy. Conclusions: Earlier onset and longer duration of SAD as well as their increased i.v.-use lead to substantial costs among allo-SCT pts who are at high risk of developing invasive mycoses. SE and PDI frequently arise from the use of lip. AmphoB, whereas caspofungin appears to be well-tolerated. Our detection of frequent SE and PDI with SAD as well as the cost analysis should help us to avoid application errors, thereby enhancing pts' safety, and to assure economically appropriate SAD use. Enrollment of additional pts is ongoing, which will be presented at the meeting. Disclosures: Neubauer: MSD Merck Sharp & Dohme GmbH: Research Funding. Engelhardt:MSD Merck Sharp & Dohme GmbH: Research Funding.

Use of Systemic Antifungal Agents In Patients with Acute Leukemia: a Prospective Analysis Covering Clinical Parameters, Side Effects, Drug Interactions and Costs

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2568-2568
Author(s):  
Barbara Metzke ◽  
Stefanie Hieke ◽  
Werner Neubauer ◽  
Hartmut Bertz ◽  
Klaus Kümmerer ◽  
...  
Keyword(s):  
Side Effects ◽  
High Risk ◽  
Acute Leukemia ◽  
Drug Interactions ◽  
Amphotericin B ◽  
Research Funding ◽  
Antifungal Drugs ◽  
Study Cohort ◽  
High Morbidity ◽  
Close Monitoring

Abstract Abstract 2568 Introduction: Invasive mycoses show high morbidity and mortality rates among immunocompromised patients (pts), and have multiplied the use and costs of systemic antifungal drugs (SAD). Especially pts with induction chemotherapy for acute leukemia and pts after allogeneic stem cell transplantation are at a high risk. This challenges physicians, as various drug-related aspects have to be considered. As side by side comparisons in unselected high-risk pts with different SAD are lacking, we prospectively analysed the frequency, clinical relevance and severity of SAD-related problems in consecutive pre- and acute leukemic pts, a 'typical', rather than highly-selected study cohort, in order to improve the efficacy and safety of SAD treatment. Methods: SAD-analysis was performed by daily participation on ward rounds, consultation of ward physicians and review of pts' medication charts and laboratory values. Pt characteristics, side effects (SE), in particular development of renal and hepatic toxicity, potential drug interactions (DI), treatment outcome and costs were assessed. SAD were given according to EORTC-adapted guidelines. Results: Currently, data from 100 consecutive pts have been obtained (AML n=71, ALL n=20, MDS n=9), these showing a median age of 59 years (range 19–75). For SAD use and their respective indications, see Table 1. The frequency of 1, 2 or 3–5 SAD regimens/pt was 56, 28 and 16, respectively, with SAD combination therapy rarely being applied (3%). Pts with relapsed leukemia (n=28) vs. with initial leukemia diagnosis (n=72) received more than one subsequent SAD in 64% vs. 36%, respectively. The importance of detailed DI analyses was stressed with a substantial median number of 22 concomitantly administered medications (range 1–50). We identified 47 potentially interacting combinations of SAD and concomitant drugs (Table 1). In total, 88% of pts receiving SAD were affected by at least one DI. SE leading to a change of SAD occurred in 13%, 10% and 6% of pts receiving lip. amphotericin B, voriconazole and posaconazole, respectively. Fluconazole, which was applied prophylactically and was low dosed in all cases, and caspofungin, showed very favourable safety profiles, necessitating no therapy adaptations. Determining renal function (RF) deterioration by comparing median eGFR values at SAD-initiation vs. after SAD-medication-end revealed a considerable eGFR decrease of 17% for lip. amphotericin B, whereas caspofungin and azole SAD had no major effects on RF. Pts with liver predamage were preferably treated with caspofungin (median baseline bilirubin level of 0.9 mg/dl compared to ≤ 0.7 mg/dl for all other agents), showing excellent tolerability. In 2009, SAD accounted for 20% of our department's inpt drug expenses, including chemotherapeutics. Median SAD costs per analysed hospital stay in our pt cohort were 2813€, with 64% of pts inducing costs higher than 1000€. According to the increased SAD use in pts with relapsed leukemia, costs in this cohort exceeded those of pts with initial diagnosis by 109% (4794€ vs. 2290€). As posaconazole is increasingly used for prophylaxis and treatment of fungal infections, we are currently obtaining serum posaconazole levels using our previously published HPLC method for quantification [Neubauer W. J Chromatogr B 2009] to ensure sufficient protection in these high-risk pts. Data on obtained serum levels will be presented at the meeting. Conclusion: This ongoing real-life analysis highlights the high number of aspects related to SAD-treatment in a high-risk pt cohort and the need for close monitoring of pts to avoid negative effects of DI and to reduce the rate of SE. By detecting and analyzing frequent DI, SE as well as pharmacoeconomic aspects, it suggests to valuably contribute to a safe, efficient and economically appropriate use of SAD. Disclosure: Metzke: MSD Merck Sharp & Dohme GmbH: Research Funding. Engelhardt:MSD Merck Sharp & Dohme GmbH: Research Funding.

Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the "Registro Italiano LMC & Campus CML"

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Mario Tiribelli ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Isabella Capodanno ◽  
Maria Cristina Miggiano ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Multivariable Analysis ◽  
Chronic Phase ◽  
Front Line ◽  
Line Therapy ◽  
Concomitant Medications

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged <45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p<0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC >100,000/mm3 vs 38.2% if WBC <100,000/mm3; p<0.001), lower Hb (53.8% if Hb <10 g/dl vs 41.9 if Hb >10 g/dl; p=0.001) and bigger spleen (65.1% if spleen >5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p<0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for >5 drugs, respectively (p<0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p<0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age > 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.

scholarly journals Current Approaches to the Treatment of Gastrointestinal Infections: Focus on Nitazoxanide

2009 ◽  
Vol 1 ◽  
pp. CMT.S2297 ◽  
Author(s):  
Jennifer L. Halsey
Keyword(s):  
Side Effects ◽  
Drug Interactions ◽  
Broad Spectrum ◽  
Safety Profile ◽  
Taenia Saginata ◽  
Gastrointestinal Infections ◽  
Oral Tablet ◽  
Acceptable Safety Profile ◽  
H Pylori ◽  
Immunocompetent Patients

Nitazoxanide is a broad-spectrum agent active against several protozoa, helminths, and bacteria, including C. difficile and H. pylori. It is available as an oral tablet and suspension, both with adequate bioavailability. Nitazoxanide is associated with minimal side effects, has an acceptable safety profile, and has been classified as a pregnancy category B agent. It is 99% protein bound, which could result in drug interactions. It is the preferred agent for the treatment of Cryptospordiosis and Giardiasis in immunocompetent patients and has shown promise for the treatment of rotavirus, mild to moderate initial C. difficile infection, refractory C. difficile infection, Amoebiasis, Blastocystosis, and Taenia saginata.

ATRA and Arsenic Trioxide (ATO) Versus ATRA and Idarubicin (AIDA) for Newly Diagnosed, Non High-Risk Acute Promyelocytic Leukemia (APL): Results of the Phase III, Prospective, Randomized, Intergroup APL0406 Study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 6-6 ◽  
Author(s):  
Francesco Lo-Coco ◽  
Giuseppe Avvisati ◽  
Sonia Maria Orlando ◽  
Felicetto Ferrara ◽  
Marco Vignetti ◽  
...  
Keyword(s):  
High Risk ◽  
Arsenic Trioxide ◽  
Research Funding ◽  
Phase Iii ◽  
Primary Study ◽  
Newly Diagnosed ◽  
Front Line ◽  
Similar Frequency ◽  
Line Therapy ◽  
The Us

Abstract Abstract 6 Background Simultaneous ATRA and chemotherapy (CHT) is the current gold standard for newly diagnosed APL resulting in ∼80% cure rates, while arsenic trioxide (ATO) is the treatment of choice for relapsed patients. ATO in variable combinations including ± ATRA ± CHT has also been tested as front-line therapy yielding encouraging results in several pilot studies as well as in two phase III studies conducted in China and the US. So far, no randomised studies have compared front-line CHT-free ATO+ATRA combination against the standard ATRA+CHT approach. Patients and Methods The phase III, randomised, prospective APL0406 trial was started in October 2007 by the Italian GIMEMA group and joined in November 2008 by the German SAL and AMLSG multicenter groups. Eligible patients were adults aged 18-<71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10×109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally reported by the MD Anderson group (Estey et al. Blood 2006, arm A), or the Italian AIDA2000 risk-adapted protocol for non high-risk disease (arm B). Patients in arm A received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in arm B received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based plus ATRA consolidation and low dose CHT and ATRA for maintenance as reported (Lo-Coco et al., Blood 2011). The primary study objective was EFS at 2 years. The study was designed to show that the rate of patients alive event-free at two years in the experimental treatment arm is at least 80%. Secondary objectives included OS, DFS, CIR rates, molecular response and toxicity profile. Results From October 2007 to September 2010, the required sample size of 162 enrolled patients was completed. Median age was 45.3 years (18.7–70.2 years) and median WBC 1.50 × 109/L. As to the Sanz's risk score, 61.8% and 38.2% of patients were in the intermediate- and low-risk categories, respectively. The two treatment arms were well balanced for main baseline characteristics including age, sex, median WBC and Sanz's score. Eight patients were not evaluable for induction due to ineligibility or protocol violation. Of 154 patients evaluable for response to induction, CR was achieved in 150 (97.4%): 75/75 (100%) in arm A vs 75/79 (95%) in arm B (P=0.12). After a median follow-up of 31 months (range 0.07–50.4) the 2 year EFS (primary objective) was 97% (C.I.95%: 93.1–100) and 86.7% (C.I.95%: 80.3–93.6) in arms A and B respectively (P=0.03). There were 1 death in CR and 2 relapses in arm A, and 7 deaths (4 in induction, 3 in CR) and 4 relapses in arm B. As to secondary objectives, OS, DFS, and CIR rates were 98.7% vs. 91.1% (P=0.03), 97% vs. 91.6% (P=0.19) and 1.6% vs. 4.3% (P=0.41) in arm A and B, respectively. Fever episodes, prolonged (>15 d) grade ≥ 3 neutropenia and thrombocytopenia were significantly more frequent in patients in arm B as compared to those in arm A (P <.001 for all comparisons). Other side effects including differentiation syndrome and increase of liver enzymes were recorded with similar frequency in the two study arms. Two patients in arm A had QTc prolongation requiring ATO discontinuation with final withdrawal in one case. PCR analysis of PML/RARA (sensitivity 10−4) was centrally performed in Rome (F. Lo-Coco) and Dresden (C. Thiede) and showed molecular CR in 141/142 (99%) of evaluable patients after completion of 3rd consolidation. One patient in arm B who tested PCR-positive at this time point was considered resistant and taken off protocol as per study design. Conclusions For patients with newly diagnosed non-high-risk APL, as compared to the standard AIDA regimen, the front-line CHT-free ATO+ATRA combination is at least not inferior for 2 year EFS. Disclosures: Lo-Coco: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Cephalon: Speakers Bureau. Off Label Use: Arsenic Trioxide (ATO) is currently approved for therapy of relapsed APL in the US and Europe. In this study the role of ATO in front-line therapy of APL is explored. Fiedler:Pfizer Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Breccia:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Platzbecker:GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Amgen: Consultancy.

New therapeutic agents in the management of HIV: an overview of darunavir for clinicians

Sexual Health ◽  
2008 ◽  
Vol 5 (3) ◽  
pp. 235 ◽  
Author(s):  
Jessica Rotty ◽  
Jennifer Hoy
Keyword(s):  
Side Effects ◽  
Hiv Infection ◽  
Protease Inhibitor ◽  
Drug Interactions ◽  
Clinical Efficacy ◽  
Safety Profile ◽  
Therapeutic Agents ◽  
Drug Resistant ◽  
Efficacy Data ◽  
Resistance Profile

This overview will provide the reader with summarised information about darunavir, a new protease inhibitor licenced for the treatment of drug resistant HIV-infection. Darunavir is a promising new drug with good clinical efficacy data and safety profile. In this overview clinicians will be updated on clinical efficacy data, side-effects, resistance profile and drug interactions. The overview should give clinicians a sound understanding of when and how to use this new protease inhibitor in the treatment of HIV-infection.

scholarly journals Real-Life Data on the Outcome of Daratumomab-Refractory Myeloma Patients: Multi-Center Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3259-3259 ◽  
Author(s):  
Noam Benyamini ◽  
Adir S ◽  
Moshe E. Gatt ◽  
Yael C Cohen ◽  
Irit Avivi ◽  
...  
Keyword(s):  
High Risk ◽  
Combination Therapy ◽  
Research Funding ◽  
De Novo ◽  
Single Agent ◽  
Real Life ◽  
Treatment Strategies ◽  
Study Patient ◽  
Line Therapy ◽  
Duration Of Response

Abstract Introduction: The survival of double refractory multiple myeloma (MM) patients was poor in the pre- monoclonal antibody era, with a median overall survival (OS) of 9 months only. Daratumumab used as a single agent has shown significant efficacy resulting in an overall response rate (ORR) of 30%, and OS of 20 months in patients, failing immunomodulatory drugs (IMIDs) and proteosome inhibitors (PIs). Daratumumab combined with pomalidomide and dexamethasone has yielded ORR of 60% and median OS of 17.5 months in such patients. Daratumumab has been recently introduced to the early relapsed MM setting, providing significant improvement in progression-free survival when administered in combination with IMIDs or PIs. The current retrospective study has evaluated the characteristics and outcome of MM patients who had progressed while being receiving daratumumab, aiming to define prognostic factors and optimal therapeutic approaches for this patient population. Methods: MM patients treated with daratumumab alone or in combinations in 11 Israeli centers between 01.2014 and 07.2018, all experiencing disease relapse/progression were included. Data including demographics, disease-related parameters at diagnosis [MM type, extramedullary disease (EMD), ISS (International Scoring System), LDH level high-risk cytogenetics], prior treatment regimens, response duration to the last pre-daratumumab therapy, treatment and outcomes post-daratumumab failure were analyzed. Results: One hundred consecutive patients progressing on daratumumab were included in the study. Patient characteristics are presented in table 1. Daratumumab was used in 2nd-3rd line therapy in 17 patients (17%), 4th in 22 patients (22%) and 5th-9th line therapy in 61 patients (61%). Sixty four patients (64%) were refractory to at least 3 novel agents before starting a daratumumab combination; 36 (36%) of them were quadrate refractory to bortezomib, carfilzomib, lenalidomide and pomalidomide. Forty five patients (45%) received daratumumab as a single agent and 55 (55%) as a combination therapy (table 1). Median duration of response to the last pre-daratumumab therapy was 5 months, with duration of ³6 months predicting response to daratumumab (P=0.019). Fifty seven percent of patients achieved stable disease or better with daratumumab combinations, with an ORR of 38% [partial response (PR) or better] and 15% achieved very good PR (VGPR) or complete response. Median time to progression on daratumumab was 3.1 months. It was shorter in patients treated with daratumumab as a single agent than in those receiving a combination therapy (2.5 vs 4.7 months, p=0.012). Progression (n=13) or de novo (n=19) EMD was recorded in 32 patients (32%). At time of relapse/progression, daratumumab was stopped in 45 patients (45%), and continued in combination with other agents in 33 patients (33%). Data regarding actions taken post-daratumumab failure were unavailable for 22 individuals. In 58 patients, for whom data regarding response to a post-daratumumab regimen were available, the ORR was 34%. Median follow-up after daratumumab failure was 8 months (0 -33.5 months), with a median OS of 5.3 months; 25% of the patients survived <2.2 months and another 25% - >14.1 months. Notably, daratumumab given in combination with chemotherapy was associated with a worse prognosis (HR=2.7, P=0.007). No OS difference was found between those who stopped daratumumab at time of failure and those who continued it. Age, gender, high-risk cytogenetics and lines of previous therapies did not affect OS in this patient group. Longer duration of response to both pre-daratumumab and daratumumab therapy was found to be associated with a prolonged OS after daratumumab failure (HR=0.929, P=0.006 and HR=0.872, P=0.024, respectively). Conclusions: The prognosis of double refractory MM patients, failing daratumumab therapy, is poor, with a median OS of 5.3 months. Post-failure continuation of daratumumab in a different anti-myeloma combination has not improved OS. Durable responses to both pre-daratumumab and daratumumab therapy are both associated with a superior OS in patients progressing on daratumumab, most probably reflecting a more favorable disease biology. Given that most patients in this study have been heavily pretreated, further evaluation of treatment strategies in patients who fail daratumumab combinations at earlier disease stages is warranted. Disclosures Cohen: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Tadmor:ABBVIE: Consultancy; JNJ: Consultancy; NOVARTIS: Consultancy; PFIEZER: Consultancy; ROCHE: Research Funding.

The Bruton Tyrosine Kinase (Btk) Inhibitor ACP-196: Marked Activity in Relapsed/Refractory CLL with a Favorable Safety Profile

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 831-831
Author(s):  
John C. Byrd ◽  
William Wierda ◽  
Jeffrey Jones ◽  
Susan O'Brien ◽  
Jennifer R. Brown ◽  
...  
Keyword(s):  
High Risk ◽  
Safety Profile ◽  
Research Funding ◽  
Response Rate ◽  
Employment Equity ◽  
Advisory Committees ◽  
Btk Inhibitor ◽  
Equity Ownership ◽  
Grade 3 ◽  
Favorable Safety

Abstract Introduction Btk is a kinase involved in B-cell receptor (BCR) signal transduction and a critical target in chronic lymphocytic leukemia (CLL). ACP-196-a potent, second generation Btk inhibitor that is more selective than the first-in-class Btk inhibitor, ibrutinib (Covey AACR2015)-has demonstrated antitumor activity in preclinical CLL models (Niemann AACR2014). Here, we present preliminary data from patients with relapsed/refractory (R/R) CLL/small lymphocytic lymphoma (SLL) enrolled in an ongoing Phase 1/2 study of single-agent ACP-196 (ClinicalTrials.gov NCT02029443). Methods and Patients This first-in-human study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics and efficacy of orally administered ACP-196 in patients with R/R CLL/SLL. Patients were continuously treated with ACP-196 at dosages ranging from 100 to 400 mg once daily (QD) as part of the dose-escalation portion of the study (4 cohorts of 6-8 patients per cohort), and 100 mg twice daily (BID) and 200 mg QD as part of the expansion portion of the study (2 cohorts). Of note, CLL patients with any degree of pancytopenia and prior exposure to PI3K inhibitors were allowed. CLL responses were investigator assessed per IWCLL criteria (modified Hallek 2008). SLL responses were investigator assessed per IWG criteria (Cheson 2007). Patients had a median age of 62 years (range 44-84), bulky lymph nodes ≥ 5 cm (47%) and median of 3 prior therapies (1-13). High-risk prognostic factors included del(17)(p13.1) 31% (18/58), del(11)(q22.3) 29% (17/58) and unmutated IGVH genes 75% (38/51). Results Results are presented through 01 June 2015 for the first 61 R/R patients, including 60 evaluable for response. The median time on study (N=61) was 10.3 (0.5-15.9) months. ACP-196 has been well tolerated with 93% (57/61) of patients continuing on study drug. Of the 4 patients who discontinued, 1 patient each discontinued due to withdrawal of consent, physician decision, unrelated AE (pre-existing, active autoimmune hemolytic anemia) and related AE (Grade 3 dyspnea). To date, no dose-related effect has been observed in frequency or severity of AEs or serious adverse events. No dose-limiting toxicities have occurred, and most AEs were Grade ≤ 2. The most common Grade 1/2 AEs (≥ 15%) were headache (39%), diarrhea (33%) and URI (16%). Grade 3/4 AEs that occurred in ≥ 3 patients were anemia (7%), pneumonia (7%) and hypertension (5%). No major hemorrhage (including subdural hematomas), atrial fibrillation, tumor lysis syndrome or pneumonitis have occurred suggesting an improved safety profile compared with other BCR and BCL-2-targeted therapies. Clinical activity has been observed in patients with R/R CLL/SLL at all doses evaluated. All patients experienced rapid reductions in lymphadenopathy. Treatment-related lymphocytosis (defined as ≥ 50% increase from baseline and above absolute lymphocyte count [ALC] of 5 K/µL) occurred in 61% (37/61) of patients and resolved in 81% (31/37) of these patients. In general, lymphocytosis peaked at a median of 3 weeks and resolved by a median of 19 weeks (range 1 to 58 weeks). The rapid decrease in lymphadenopathy and treatment-related lymphocytosis along with concurrent improvement in baseline cytopenias has led to a high proportion of partial responses (PRs) early in treatment (Figure 1). Best overall response rate including PR and PR with lymphocytosis (PR+L) was 93% (PR=70%, PR+L=23%, SD=7%, PD=0%). For patients with del(17)(p13.1), the response rate was 100% (PR=72%, PR+L=28%). In the 4 patients with prior idelalisib therapy, the response rate also was 100% (PR=75%, PR+L=25%). To date, no disease progression or Richter's transformation has occurred (Figure 2). Pharmacokinetic results showed exposure of ACP-196 was dose proportional with no drug accumulation. At dosages as low as 100 mg QD, pharmacodynamic results showed low intra-patient variability, high Btk occupancy (> 90% over 24 hr) and high phospho-Btk inhibition (> 90% over 24 hr). Conclusion ACP-196 is a highly potent and selective oral Btk inhibitor with a favorable safety profile. Responses occur early in treatment with no disease progression to date either in heavily pretreated patients or those with high-risk prognosis factors. ACP-196 is currently in Phase 3 trials for TN (ClinicalTrials.gov NCT0247568) and R/R high-risk CLL (ClinicalTrials.gov NCT02477696). Disclosures Byrd: Acerta Pharma BV: Research Funding. Jones:Acerta Pharma BV: Research Funding. O'Brien:Acerta Pharma BV: Research Funding. Schuh:Acerta Pharma BV: Research Funding. Hillmen:Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Acerta Pharma BV: Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Stephens:Immunomedics: Research Funding; Acerta Pharma BV: Research Funding. Ghia:Pharmacyclics: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Acerta Pharma BV: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Devereux:Acerta Pharma BV: Research Funding. Chaves:Acerta Pharma BV: Research Funding. Barrientos:Acerta Pharma BV: Research Funding. Wang:Acerta Pharma BV: Employment, Equity Ownership. Huang:Acerta Pharma BV: Employment, Equity Ownership. Covey:Acerta Pharma BV: Employment, Equity Ownership, Patents & Royalties. Navarro:Acerta Pharma BV: Employment, Equity Ownership. Rothbaum:Acerta Pharma BV: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties. Hamdy:Acerta Pharma BV: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau.

scholarly journals Surpass-ET Trial: A Phase 3, Open-Label, Multicenter, Randomized, Active-Controlled Study to Assess Pharmacokinetics and Compare the Efficacy, Safety, and Tolerability of P1101 Vs Anagrelide As Second Line Therapy for Essential Thrombocythemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1491-1491
Author(s):  
Ruben A. Mesa ◽  
Norio Komatsu ◽  
Harinder Gill ◽  
Jie Jin ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
High Risk ◽  
Sample Size ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Controlled Study ◽  
Second Line ◽  
Open Label ◽  
Second Line Therapy ◽  
Phase 3 ◽  
Line Therapy

Abstract Background: Essential thrombocythemia (ET) is a subtype of chronic myeloproliferative neoplasms (MPN) characterized by thrombocytosis and disease-related symptoms, which may be difficult to manage. Patients with ET are also at higher risk of thrombosis and hemorrhage. Ideal therapeutic approaches should achieve adequate cytoreduction, reduce the risk of thrombo-hemorrhagic complications, and prevent progression to post-ET myelofibrosis (PET-MF) or secondary acute myeloid leukemia (AML). Low-dose aspirin with hydroxyurea (HU) is typically given as first-line therapy in high-risk patients. However, approximately 20-40% of ET patients become HU-intolerant or -resistant. In ET, resistance and/or intolerance portend an increased risk of thrombosis, hemorrhage, disease transformation and death. There is a paucity of prospective clinical trial data to guide management of ET patients who are HU resistant or intolerant. P1101 is a next generation monopegylated interferon (IFN) alfa-2b, developed specifically to treat MPNs, including ET. Study Design and Methods: The SURPASS-ET trial (NCT04285086) is a Phase 3, open-label, multicenter, randomized, active-controlled study to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of P1101 after 12 months of treatment compared with anagrelide as second line therapy for subjects with ET who have shown resistance or intolerance to HU. The primary endpoint is durable modified ELN composite response at 9 and 12 months from dosing. Cochran-Mantel-Haenszel test will be used for comparing the primary endpoint in the two treatment arms. The PK parameters of P1101, including (but not limited to) C min, T max, C max, and area-under-curve (AUC) will be derived using PPK analysis and the relationship between exposure and efficacy and safety endpoints will be examined using E-R analysis. Evaluation of efficacy will include clinical laboratory assessments, allelic burden measurements of CALR, JAK2, and MPL, spleen size measurements, bone marrow sampling (optional), EQ-5D-3L, and MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) assessments. A total of 130 randomized subjects is planned to detect a difference of 40% (P1101) versus 15% (anagrelide) in durable ELN response rate with 90% power at alpha level = 0.05 using the chi-square test. To account for possible non-evaluability (e.g., no follow-up data), approximately 160 subjects will be randomized in this study to get 130 completed patients. Because of uncertainty in the assumptions on which the calculation of the sample size is based, an interim analysis for sample size adjustment will be implemented. Major inclusion criteria include subjects diagnosed with high-risk ET (either older than 60 years and JAK2V617F-positive at screening or having disease-related thrombosis or hemorrhage in the past), diagnosed according to the World Health Organization (WHO) 2016 criteria, documented resistance/intolerance to HU and IFN naïve or anti-P1101 binding antibody negative. Key exclusion criteria include pregnant females, significant cardiovascular disease, documented autoimmune disease and a history or presence of clinically significant depression or neurological disease. The study involves approximately 65 sites across the US, Taiwan, Japan, China, Hong Kong, Singapore, S. Korea, Canada, and Europe. To-date 55 patients (54 Asians, 1 Caucasian) have been randomized. The mean and median age at recruitment was 58.9 years (SD: 14.34) and 63 years (range 21 to 80 years) respectively. Twenty-seven men (49.1%) and twenty-eight women (50.9%) were recruited. Forty-two subjects (76.4%) had a TSS &lt; 20. The study is being overseen by a Data Safety Monitoring Board (DSMB). Figure 1 Figure 1. Disclosures Mesa: Gilead: Research Funding; Promedior: Research Funding; AOP: Consultancy; Incyte Corporation: Consultancy, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; La Jolla Pharma: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy, Research Funding; Samus: Research Funding; Pharma: Consultancy; CTI: Research Funding; Celgene: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; CTI: Research Funding. Komatsu: Fujifilm Wako Pure Chemical Corporation: Research Funding; Fuso Pharmaceutical Industries, Ltd.: Research Funding; Japan Tobacco Inc.: Consultancy; Otsuka Pharmaceutical Co. Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma KK: Consultancy, Research Funding, Speakers Bureau; Shire Japan KK: Consultancy, Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Consultancy, Current Employment, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding. Sato: PharmaEssentia Japan KK: Current Employment. Qin: PharmaEssentia Corp.: Current Employment. Urbanski: PharmaEssentia Corporation: Current Employment. Shih: PharmaEssentia Corporation: Consultancy. Zagrijtschuk: PharmaEssentia U.S.A. Corp.: Current Employment. Zimmerman: PharmaEssentia Corporation: Current Employment. Verstovsek: Gilead: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Ital Pharma: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

scholarly journals Rhabdomyolysis Following Initiation of Posaconazole Use for Antifungal Prophylaxis in a Patient With Relapsed Acute Myeloid Leukemia

2017 ◽  
Vol 5 (1) ◽  
pp. 232470961769074 ◽  
Author(s):  
Mayur D. Mody ◽  
Deepak Ravindranathan ◽  
Harpaul S. Gill ◽  
Vamsi K. Kota
Keyword(s):  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
High Risk ◽  
Acute Leukemia ◽  
Drug Interactions ◽  
Clinical Data ◽  
Myeloid Leukemia ◽  
Antifungal Prophylaxis ◽  
Relapsed Acute Myeloid Leukemia ◽  
Acute Myeloid

Posaconazole is a commonly used medication for antifungal prophylaxis in patients with high-risk acute leukemia, such as acute myeloid leukemia. Despite clinical data that show that posaconazole is superior to other antifungal prophylaxis medications, posaconazole is known to have many side effects and drug-drug interactions. We present a patient who developed rhabdomyolysis after being started on posaconazole for prophylaxis in the setting of relapsed acute myeloid leukemia.

Treatments and Outcomes of Patients with Multiple Myeloma (MM) Older Than 75 Years of Age: A Single Institution Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4756-4756
Author(s):  
Elizabeth Finley-Oliver ◽  
Kenneth Shain ◽  
Taiga Nishihori ◽  
Jose-Leonel Ochoa-Bayona ◽  
Melissa Alsina ◽  
...  
Keyword(s):  
Older Adults ◽  
High Risk ◽  
Research Funding ◽  
Novel Agents ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
High Risk Disease ◽  
Causes Of Mortality ◽  
Competing Causes

Abstract Abstract 4756 Background: Considerable advances in the treatment of myeloma patients have culminated in the approval of novel agents (thalidomide, bortezomib, lenalidomide) with survival benefits noted for each. The outcomes of patients younger than 65 years have been shown to be improved with the availability of novel therapies. However, older adults, who comprise the majority of patients with myeloma, have not experienced the same improvement in outcomes as noted in epidemiologic studies (Brenner et al. Hematologica 2009. 94(2): 270 and Schaapveld et al, Eur J Cancer. 2009. 46(1):160.). We postulated that lack of access to novel agents, difference in disease biology, or competing causes of mortality might explain this finding. Method: We conducted a retrospective review of electronic medical records for patients 75 years of age or older at the time of diagnosis with symptomatic myeloma after 2004 (to allow for the availability of novel agents). Demographic information including comorbid conditions, disease characteristics (including risk features and cytogenetics), treatment information as well as survival data was collected. Risk stratification (standard or high risk) was based on the Mayo criteria (Steward et al. Leukemia 2007; 21: 529). Result: 72 patients (median age 78 years, range 75–89, 58% were older than 80 years) with symptomatic myeloma were the subjects of this study. Seventy-two percent were males and 28%, 15%, 60% and 29% had a history of cardiac dysfunction (defined as CAD or CHF), diabetes, hypertension and another malignancy (excluding non melanoma skin cancer) respectively. While 31 patients had missing information to determine the International Staging System; 29%, 32% and 39% had ISS stages 1, 2, and 3, respectively (similar to what is expected in younger cohorts). Moreover, using the Mayo risk model, 31% of patients had high risk disease. The median number of systemic therapies received was 2 (range 0–6). First line therapy did not include a novel agent in 29% of patients (who received alkylating agents 12%, anthracyclines 4%, corticosteroids alone 13%) and at the time of relapse, all but 4 patients had received a novel agent. First line therapy consisted of lenalidomide based regimens (30%), bortezomib based regimens (12%), thalidomide based regimens (28%) and a combination of novel agents (1%). The median overall survival for the entire cohort was 46 months (95% CI: 36.4–56.2 months). Conclusion: Older adults (greater than 75 years of age) with multiple myeloma continue to experience a shortened survival despite the use of novel agents and without a discernable higher incidence of high risk disease suggesting competing causes of mortality and tolerance to therapy may significantly limit the benefit of novel therapies in this age group. To address these limitations, we have initiated a clinical trial evaluating a sequential response adapted lenalidomide based therapy for older adults with newly diagnosed myeloma in order to minimize treatment related toxicities. Disclosures: Alsina: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Baz:celgene: Consultancy, Research Funding; millenium: Research Funding; orthobiotec: Research Funding.

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