Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.

1993 ◽  
Vol 11 (9) ◽  
pp. 1652-1660 ◽  
Author(s):  
A F List ◽  
C Spier ◽  
J Greer ◽  
S Wolff ◽  
J Hutter ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Response Rate ◽  
Chronic Phase ◽  
Response To Treatment ◽  
Mdr1 Gene ◽  
Gene Transcript ◽  
Blood Concentrations ◽  
P Glycoprotein ◽  
Dose Dependent

PURPOSE To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. PATIENTS AND METHODS Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [i.v.]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. RESULTS Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephrotoxic antibiotics. Steady-state blood concentrations of CsA > or = 1,500 ng/mL were achieved in all patients receiving CI doses > or = 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. CONCLUSION High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.

P-Glycoprotein (Pgp) - Dependent Drug Resistance to Imatinib at CML-BC Is Exclusively Developed in Aggressive Minor Blast Subpopulation (MS) and Can Be Reversed by Pgp Modulators

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 721-721
Author(s):  
Hanan Galski ◽  
Masha Simanovsky ◽  
Sagi Berlinsky ◽  
Arnon Nagler
Keyword(s):  
Drug Resistance ◽  
Abc Transporter ◽  
Blast Crisis ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Mdr1 Gene ◽  
Activity Levels ◽  
Dependent Manner ◽  
Proposed Model ◽  
Dose Dependent

Abstract CML is considered as a model of multi step-developing malignancies. Although very effective in chronic phase CML, imatinib mesylate (IM) and second generation TK inhibitors treatment are usually less effective in advanced CML (accelerated and blast crisis phases) since drug-resistant clones inevitably shortly emerge. In a recent study (Simanovsky M et al, Differentiation. 2008 Apr 29 [Epub ahead of print]), we have demonstrated that at blast crisis CML (CML-BC), blood circulating blasts of the same CML clone are heterogeneous, containing a small cell-fraction (1–3%) of blasts that are significantly more aggressive than the major malignant population. Briefly, we found that these minor subsets (MS) of blasts (both from patients and human CML-BC cell lines) have a typical highly repopulating ability, increased clonogenicity, and over expression of BCR-ABL and few other cancer-related genes. To evaluate whether the MS blasts also exhibit differential drug resistance mechanisms toward IM, we compared the two blast subsets for the level of resistance to IM in relation to expression of a functional Pgp, an ABC transporter that is the product of the ABCB1 (MDR1) gene. In the current study, we found that the MDR1 gene (but not several other ABC transporter genes) is significantly (5–7 fold) upregulated in the MS blasts, relatively to the major population. Moreover, FACS and Western analyses revealed that while Pgp could not be detected on the cell surface of the major blast subsets, Pgp is exclusively highly expressed in the MS blasts. Moreover, functional Pgp assays in the MS blasts (efflux, dose-dependent competitions, and UIC2 Pgp-specific shift assays) indicated unequivocally that IM is a substrate for Pgp. While IM efficiently inhibited the proliferation of the major blasts in dose-dependent manner, the proliferation rate of the MS blasts was essentially not affected. Furthermore, the anti-proliferative effect of IM on the MS blasts could be restored by addition of the Pgp inhibitor, R-verapamil, in dose-dependent manner. While relatively long, gradual selection in culture of the major CML-BC subsets resulted in some Pgp-independent IM-resistant clones, Pgp activity levels were shortly further elevated (by 1-order magnitude) in the MS blasts. Interestingly, FACS analyses, using different monoclonal antibodies that bind specifically to different known extra cellular epitopes of Pgp, indicated differential antibodies-epitopes binding ratios after IM selection. These stoichiometric changes suggest a topological folding shift of Pgp between its moderate to high activity (proposed model, Figure 1). In conclusion, the existence of a minor “pool” of CML blasts of both greater clonogenicity and high expression and activity levels of Pgp, apparently signify clonal evolution toward both increased malignancy and lower therapeutic sensitivity. Moreover, as both IM and Dasatinb are transported by Pgp, this study suggests that their combination therapy with Pgp-modulateors might also be clinically effective in targeting this aggressive blast population. FIGURE 1: The proposed model of topological folding of Pgp in relation to activity. FIGURE 1:. The proposed model of topological folding of Pgp in relation to activity.

Phase I Evaluation of Prolonged-Infusion Gemcitabine With Irinotecan for Relapsed or Refractory Leukemia or Lymphoma

2002 ◽  
Vol 20 (13) ◽  
pp. 2995-3000 ◽  
Author(s):  
Adam J. Bass ◽  
Jon P. Gockerman ◽  
Eve Hammett ◽  
Carlos M. DeCastro ◽  
David J. Adams ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Acute Leukemia ◽  
Phase I ◽  
Phase I Trial ◽  
Overall Response Rate ◽  
Response Rate ◽  
Total Duration ◽  
Hematologic Malignancies ◽  
Prolonged Infusion ◽  
Induction Regimen

PURPOSE: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m2/min in combination with irinotecan at 40 mg/m2 daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma. PATIENTS AND METHODS: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin’s lymphoma. Patients received irinotecan at 40 mg/m2 daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m2/min, with the total duration adjusted following a modified continuous reassessment model. RESULTS: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m2/min (7,200 mg/m2). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%). CONCLUSION: A prolonged infusion of gemcitabine at 10 mg/m2/min for 12 hours with 3 days of irinotecan at 40 mg/m2/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

scholarly journals Multidrug Resistance Gene (MDR1) Polymorphism and Response to Nilotinib in Egyptian Patients with Chronic Myeloid Leukemia (CML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5220-5220
Author(s):  
Mervat Mattar ◽  
Hend Ellithy ◽  
Yasser Elnahas ◽  
Mohamed osman Azzazi
Keyword(s):  
Multidrug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Response To Treatment ◽  
Mdr1 Gene ◽  
Molecular Response ◽  
Multidrug Resistance Gene ◽  
Significant Difference

Abstract Introduction: Inappropriate expression of the multidrug resistance (MDR1) gene I in chronic phase chronic myeloid leukemia cases (CML-CP) encodes P glycoprotein (Pgp)that may cause resistance to second generation tyrosine kinase inhibitors (TKIs) Patients and methods: Thirty-one upfront CML-CP patients, planned to receive nilotinib, were included. Detection of MDR1 gene polymorphism C3435T, using PCR Restriction Fragment Length Polymorphisms (PCR-RFLP) was done initially for every patient. We prospectively followed up the patients between February 2012 and February 2014 with PCR for BCR-ABL1 transcripts every 3 months. The molecular response to nilotinib, according to the level of BCR-ABL1 by PCR, was compared to the different MDR1 3435 genotypes. Results: The majority of the patients carried the MDR1 3435CC genotype of Molecular response was optimal in 56%, 60% and 80% of the patients at month 3, 6 and 12 respectively.There was no statistically significant difference between MDR- C3435T genotypes and the molecular response to treatment with nilotinib. Disclosures No relevant conflicts of interest to declare.

scholarly journals Results of a Phase I/II Study of DFP-10917, a Nucleoside Analog, Given By Continuous Infusion (CI) in Patients (pts) with Relapsed or Refractory Acute Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3804-3804 ◽  
Author(s):  
Hagop Kantarjian ◽  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Tapan Kadia ◽  
Courtney DiNardo ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Safety Profile ◽  
Response Rate ◽  
Cancer Center ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
University Of Texas ◽  
Md Anderson ◽  
Stage 1

Abstract Background: DFP-10917 is a nucleoside analog similar to cytarabine with a unique mechanism of action upon prolonged administration at a low dose. Under such administration, DFP-10917 is converted to its nucleotide form and then incorporated into tumor DNA to cause DNA strand breaks resulting in G2/M phase-arrest by cell-checkpoint regulators and ultimately the apoptosis of tumor cells. Methods: In Phase I, DFP-10917 was administered by 7-day CI followed by 21 days rest (P1-stage 1) or 14-day CI followed by 14 days rest (P1-stage 2) in pts with relapsed or refractory acute leukemia to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and dose-limiting toxicity (DLT) of CI DFP-10917. Phase 2 was an open label, single arm, two-stage study of DFP-10917 administration at the RP2D using a 14-day CI in pts with relapsed or refractory acute myeloid leukemia (AML), or newly diagnosed AML pts aged 60 years or older . The study design assumed that a response rate (CR, CRi, CRp and PR) of at least 20% would justify further study of DFP-10917, based on a Simon two-stage optimal design (i.e., > 1/10 pts respond in P2-stage 1, then an additional 19 pts to be enrolled in P2-stage 2). Overall, if > 4/29 pts respond, DFP-10917 warrants further investigation. Results: In P1-stage 1, 27 pts received a 7-day CI of DFP-10917 at eight escalating doses ranging from 4 to 35 mg/m2/day. At the 35 mg/m2 dose level, one patient experienced a cycle 1 DLT of grade 3 diarrhea. The starting dose for P1-stage 2 was calculated as two-thirds the cumulative 7-day DFP-10917 dose at the MTD of 30 mg/ m2/day divided by 14-day resulting in a dose of 10 mg/m2/day x 14 days. In P1-stage 2, the 10 mg/m2/day x 14-day CI dose resulted in DLTs of prolonged hypo-cellularity in 2 of 4 pts. At the 6 mg/m2/day x 14-day dose level, 1 of 6 evaluable pts in a cohort experienced a DLT of prolonged hypo-cellularity, and the MTD/RD was defined as 6 mg/m2/day x 14-day CI. Initial efficacy assessments for P1-stage 2 include leukemia responses observed in 7 of 10 pts (70%) receiving the 14-day DFP-10917 CI; 3 were bone marrow complete responses, and 4 were partial responses. One patient has received more than 11 cycles of DFP-10917 CI to date with ongoing CR. In P2-stage 1, 10 pts (8 salvage AML, 2 first-treatment for AML) were treated with the RP2D. 5 pts (50%) demonstrated responses; 2 pts had CR, including 1 patient that transitioned to stem cell transplantation (SCT), 1 patient had CRi, 2 patients had marrow CRs, including one patient that transitioned to SCT, and 1 patient with an early marrow response died of pneumonia. The P2-stage 2 is to enroll an additional 19 pts and enrollment is ongoing. There have been no deaths related to DFP-10917 treatment to date. Conclusions: The RP2D of DFP-10917 in relapsed AML was established at 6 mg/m2/day for 14-day CI. In Phase 2, DFP-10917 demonstrates significant activity with a 50% response rate and a tolerable safety profile in relapsed or refractory AML, or pts aged ≥ 60 years with newly diagnosed AML. The final response rate and safety profile of DFP-10917 for the Phase 2 study will be presented. Disclosures DiNardo: Novartis: Research Funding. Waukau:The University of Texas MD Anderson Cancer Center: Employment. Kwari:The University of Texas MD Anderson Cancer Center: Employment. Iizuka:Delta-Fly Pharma, Inc.: Employment. Jin:Delta-Fly Pharma, Inc.: Employment.

scholarly journals PIM2 and NF-κβ gene expression in a sample of AML and ALL Egyptian patients and its relevance to response to treatment

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shymaa Kamal El Din Abed El Rahman ◽  
Sanaa Sayed Abd Elshafy ◽  
Mohamed Samra ◽  
Hala Mohammed Ali ◽  
Rabab Afifi Mohamed
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Response To Treatment ◽  
Control Group ◽  
Poor Overall Survival ◽  
Healthy Control ◽  
Complete Blood Counts

Abstract Background The relation between PIM2 and the transcriptional factor NF κβ have been controversial in literature. The significance of PIM2 and NF-κβ genes expression on the incidence of acute leukemia (AML and ALL) and its relevance to the response rate was evaluated. Sixty de novo acute leukemia patients were stratified in 2 groups: 30 acute myeloid leukemia (AML) and 30 acute lymphoblastic leukemia (ALL) patients and compared to 30 sex- and age-matched controls. The expression level of PIM2 and NF κβ genes was measured using quantitative real-time polymerase chain reaction (QRT-PCR). The patients were followed with clinical examination and complete blood counts. Results The expression level of PIM2 gene was significantly higher in AML patients (P<0.001) compared to the control group. The mean expression level of NF κβ gene was significantly high in AML and ALL patients compared to the healthy control group (P=0.037 and P<0.001; respectively). The overall survival in AML patients was higher in NF κβ gene low expressers compared to high expressers (P=0.047). The number of AML patients who achieved complete remission was significantly higher in PIM2 gene low expressers in comparison to PIM2 gene high expressers (P=0.042). Conclusion PIM2 and NF κβ genes might have a role in the pathogenesis of acute leukemia, poor overall survival, and failure of response to induction therapy.

scholarly journals Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kai-Lin Yang ◽  
Mau-Shin Chi ◽  
Hui-Ling Ko ◽  
Yi-Ying Huang ◽  
Su-Chen Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Response Rate ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Normal Liver ◽  
Maximum Tolerated Dose ◽  
Outcome Analysis ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc

Abstract Background To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1–3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC). Methods This phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local–regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS). Results Total nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months. Conclusions Axitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort. Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461

Effect of Clarithromycin on Steady-State Digoxin Concentrations

2003 ◽  
Vol 37 (2) ◽  
pp. 178-181 ◽  
Author(s):  
Hideko Tanaka ◽  
Kana Matsumoto ◽  
Kazuyuki Ueno ◽  
Mayumi Kodama ◽  
Kohji Yoneda ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Digoxin Concentration ◽  
Concomitant Administration ◽  
Percentage Increase ◽  
P Glycoprotein ◽  
Before And After ◽  
Glycoprotein Inhibitors ◽  
Dose Dependent ◽  
Digoxin Therapy

OBJECTIVE: To evaluate the magnitude and dose-relatedness of the effect of clarithromycin on the pharmacokinetics of digoxin, and to compare the effects of clarithromycin with those of P-glycoprotein inhibitors. METHODS: Eight Japanese inpatients with congestive heart failure participated in this study. Each patient received oral digoxin therapy for at least 7 days and were coadministered oral clarithromycin to prevent or treat pneumonia. To evaluate the effects of clarithromycin on the pharmacokinetics of digoxin, digoxin concentrations were compared before and after coadministration of clarithromycin. RESULTS: Digoxin concentrations were higher after coadministration of clarithromycin in all patients (before, 0.838 ± 0.329 ng/mL; after, 1.36 ± 0.619 ng/mL); (p < 0.005). A significant correlation was observed between the dose of clarithromycin and the percentage of increase in the digoxin concentration. CONCLUSIONS: Digoxin concentrations increased during concomitant administration of clarithromycin, and this effect was dose-dependent on clarithromycin. The percentage increase in digoxin concentrations after the usual oral dose of clarithromycin (400 mg/d) is approximately 70%. Therefore, digoxin concentrations must be monitored carefully after coadministration of clarithromycin, and the doses of digoxin may need readjustment in patients who are concomitantly receiving clarithromycin.

scholarly journals MDR1 gene polymorphisms and P-glycoprotein expression in respiratory diseases

2015 ◽  
Vol 159 (3) ◽  
pp. 341-346 ◽  
Author(s):  
Maja Milojkovic ◽  
Nena Milacic ◽  
Jelena Radovic ◽  
Srdjan Ljubisavljevic
Keyword(s):  
Gene Polymorphisms ◽  
Respiratory Diseases ◽  
Mdr1 Gene ◽  
P Glycoprotein

scholarly journals The Weighed Core Symptom Scale and Prediction of ADHD in Adults – Objective Measures of Remission and Response to Treatment with Methylphenidate

2013 ◽  
Vol 9 (1) ◽  
pp. 171-179
Author(s):  
Hanna Edebol ◽  
Lars Helldin ◽  
Torsten Norlander
Keyword(s):  
Adult Adhd ◽  
Response Rate ◽  
Optimal Dose ◽  
Response To Treatment ◽  
Therapeutic Effects ◽  
Modified Release ◽  
Symptom Scale ◽  
Core Symptom ◽  
Two Measures

Objective: Two measures of the response rate and the optimal treatment response for adult ADHD were evaluated using methylphenidate. The hypotheses were that Prediction of ADHD (PADHD) defines remission, the Weighed Core Symptom (WCS) scale registers direct effects of medication and that WCS may indicate the optimal dose level during titration. Design: PADHD and WCS were analyzed at baseline and after intake of low doses of either short-acting or modified-release formulations of methylphenidate, MPH (Study I), during titration with modified-release formulations of MPH (18/27, 36, 54, 72 mg) and at three months follow-up (Study II). Patients: Study I consisted of 63 participants (32 females) and Study II consisted of 10 participants (6 females) diagnosed with ADHD and who was to start with treatment. Outcome measures: Prediction of ADHD (PADHD) indicates the occurrence of ADHD (No, Yes) and the Weighed Core Symptom scale (WCS) quantifies ADHD from 0 to 100 (max-min). Results: The number of clinical cases of ADHD decreased after methylphenidate treatment according to PADHD. WCS increased (p < 0.001) from 9.75 (SD = 12.27) to 47.50 (SD = 29.75) with about 10 mg of methylphenidate (N = 63). During titration, symptoms improved after 18/27 mg and 36 mg of methylphenidate and baseline-follow up comparisons showed WCS increments (p = 0.005) from 31.00 (N = 10, SD = 26.85) to 69.00 (N = 10, SD = 22.34). Conclusions: PADHD defined remission and WCS measured therapeutic effects of methylphenidate in adult ADHD.

Sign in / Sign up

Export Citation Format

Share Document