scholarly journals High dose pollen intralymphatic immunotherapy: two RDBPC trials question the benefit of dose increase

2021 ◽  
Author(s):  
Laila Hellkvist ◽  
Eric Hjalmarsson ◽  
Dan Weinfeld ◽  
Alsog Dahl ◽  
Agneta Karlsson ◽  
...  
Keyword(s):  
Grass Pollen ◽  
De Novo ◽  
Symptom Control ◽  
High Dose ◽  
Double Blind ◽  
Dosing Schedule ◽  
Intralymphatic Immunotherapy ◽  
Immunological Effects ◽  
High Doses ◽  
Cell Changes

Background The same dosing schedule, 1000 SQ-U times three, with one-month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies aimed to evaluate if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety. Methods Two randomized double-blind placebo-controlled trials of ILIT for grass pollen induced AR were performed. The first included 29 patients that had recently ended 3 years of SCIT and the second contained 39 not previously vaccinated patients. An up-dosage of 1000-3000-10 000 SQ-U with one month in between was evaluated. Results ILIT in doses up to 10 000 SQ-U was safe after recent SCIT. The combined symptom-medication scores (CSMS) were reduced by 31% and the grass specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ-U. A modified up-dosing schedule; 1000-3000-3000 SQ-U appeared to be safe but failed to improve the CSMS, quality of life and nasal provocation response. Flow cytometry analyses could not detect any T-cell changes, while lymph node derived dendritic cells showed increased activation. Conclusion ILIT in high doses after SCIT appears to further reduce grass pollen induced seasonal symptoms and may be considered as an add-on treatment for patients that do not reach full symptom control after SCIT. Up-dosing schedules de novo with three monthly injections that exceeds 3 000 SQ-U should be avoided.

scholarly journals High dose pollen intralymphatic immunotherapy: two RDBPC trials question the benefit of dose increase

2021 ◽  
Author(s):  
Lars Olaf Cardell ◽  
Laila Hellkvist ◽  
Eric Hjalmarsson ◽  
Dan Weinfeld ◽  
Alsog Dahl ◽  
...  
Keyword(s):  
Grass Pollen ◽  
De Novo ◽  
Symptom Control ◽  
High Dose ◽  
Double Blind ◽  
Dosing Schedule ◽  
Intralymphatic Immunotherapy ◽  
Specific Igg4 ◽  
Immunological Effects ◽  
High Doses

Background The same dosing schedule, 1000 SQ-U times three, with one-month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies evaluated if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety. Methods Two randomized double-blind placebo-controlled trials of ILIT for grass pollen induced AR were performed. The first included 29 patients that had recently ended 3 years of SCIT and the second contained 39 not previously vaccinated patients. An up-dosage of 1000-3000-10 000 (5000 + 5000 with 30 minutes apart) SQ-U with one month in between was evaluated. Results Doses up to 10 000 SQ-U was safe after recent SCIT. The combined symptom-medication scores (CSMS) were reduced by 31% and the grass specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ-U. A modified up-dosing schedule; 1000-3000-3000 SQ-U appeared to be safe but failed to improve the CSMS. Flow cytometry analyses showed increased activation of lymph node derived dendritic but not T-cells. Quality of life and nasal provocation response did not improve in any study. Conclusion ILIT in high doses after SCIT appears to further reduce grass pollen induced seasonal symptoms and may be considered as an add-on treatment for patients that do not reach full symptom control after SCIT. Up-dosing schedules de novo with three monthly injections that exceeds 3 000 SQ-U should be avoided.

CTIM-28. MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, FOR RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi56-vi57
Author(s):  
John Sampson ◽  
Achal Singh Achrol ◽  
Manish K Aghi ◽  
Krystof Bankiewiecz ◽  
Martin Bexon ◽  
...  
Keyword(s):  
De Novo ◽  
Symptom Control ◽  
Recurrent Glioblastoma ◽  
Interleukin 4 ◽  
External Control ◽  
High Dose ◽  
Open Label ◽  
Convection Enhanced Delivery ◽  
High Concentrations ◽  
Dose Volumes

Abstract BACKGROUND MDNA55 is an IL4R-targeted toxin in development for treatment of recurrent glioblastoma (rGBM). MDNA55 binds to IL4R expressed by tumor cells and non-malignant cells of the tumor microenvironment. METHOD MDNA55-05 was an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in patients with 1st or 2nd recurrence following de novo GBM, IDH wild type status and not indicated for resection at relapse. Dose volumes (up to 60mL) and concentration of MDNA55 (1.5 to 9.0 μg/mL) were studied. RESULTS MDNA55 showed an acceptable safety profile at all doses tested. Median OS (mOS) amongst all subjects was 11.9 months, OS-24 was 20%, and PFS-12 was 27%. Among subjects expressing high levels of IL4R (irrespective of MDNA55 dose) and low levels of IL4R expression administered high dose (≥ 180μg) of MDNA55 (IL4Rhi + IL4Rlo/hd), mOS further improved to 14.0 months with OS-24 of 20%. Unmethylated MGMT promoter status did not affect MDNA55 treatment outcomes. In the IL4Rhi + IL4Rlo/hd population (N=17), mOS was 14.9 months with OS-24 of 22%. Following treatment with high concentrations of MDNA55 (6.0 or 9.0 μg/mL), transient (median of 3 cycles) low dose Avastin (5mg/kg q2w or 7.5mg/kg q3w) was used for symptom control and steroid sparring. Among these subjects, mOS amongst all comers (N=9) and the IL4Rhi + IL4Rlo/hd group (N=8) increased to 21.8 and 18.6 months with OS-24 of 44% and 38%, respectively. CONCLUSIONS MDNA55 shows potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. In the 1:1 randomized Phase 3 trial, the study will enrol two-thirds of subjects in the SOC arm from a matched external control arm. Unlike conventional RCTs, the hybrid design sets a new precedent for GBM trials, allowing robust OS analysis while significantly reducing the number of subjects randomized to SOC arm.

scholarly journals Astarabine, a Novel Leukemia-Targeted Cytarabine Composition Allows, for the First Time, the Delivery of High Cytarabine Doses for Older or Unfit Patients with Acute Leukemia. Results of an Ongoing Phase I/IIa Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1650-1650
Author(s):  
Tsila Zuckerman ◽  
Stela Gengrinovitch ◽  
Ruth Ben-Yakar ◽  
Ron Hoffman ◽  
Israel Henig ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
De Novo ◽  
Intensive Therapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Unfit Patients ◽  
Equity Ownership ◽  
High Doses

Abstract Introduction: Therapy of acute myeloid leukemia (AML) has not changed significantly during several decades. High-dose cytarabine, although used as the first-line treatment for AML since 1970s and as a second-line treatment for acute lymphoblastic leukemia (ALL), is associated with severe side effects, such as cerebellar toxicity and bone marrow suppression. Hence, while the incidence of AML increases with age, doses of cytarabine are significantly attenuated or the drug is entirely excluded from the regimen used in older adults due to its potential toxicities, particularly in individuals with hepatic or renal dysfunction. Astarabine is a new composition of cytarabine covalently bound to asparagine. It is designed to target cytarabine to leukemic blasts, thus avoiding extramedullary toxicity. Leukemic cells, which are dependent on an external source of amino acids in general and asparagine in particular, due to their high metabolic rate, have a relatively increased uptake of Astarabine. Inside the blasts, Astarabine is cleaved to cytarabine, enabling targeted killing and relative sparing of normal hematopoiesis. As such, Astarabine may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults who otherwise can be given supportive therapy only. The aim of this study was to evaluate the safety and optimal dose of Astarabine in refractory/relapsed or medically unfit patients with acute leukemia. Methods: This Phase I/IIa prospective open label study enrolled patients aged ≥18 years with relapsed/refractory or newly-diagnosed acute leukemia unfit for intensive therapy, as judged by the treating physician. The study was approved by the Rambam IRB (approval #0384-11). Patients were enrolled into 6 Astarabine escalating-dose cohorts, each composed of 3-6 patients. Treatment was administered as a 1-hour single daily infusion for 6 days. For cohorts 1-4, Astarabine doses for each infusion were 0.5g/m2, 1.5g/m2, 3g/m2 and 4.5g/m2. The doses were reduced by 50% for patients >50 years. Since dose limiting toxicity (DLT) was not reached in cohorts 1-4, the study was extended to include cohorts 5 and 6 with daily Astarabine doses of 4.5g/m2 and 6g/m2, respectively, with no dose reduction for patients >50 years old. Results: The outcome of 15 patients is reported herein. Six patients with a median age of 64 years (range 27-81) had refractory/relapsed AML, 9 patients with a median age of 80 years (range 70-90) were newly diagnosed (secondary AML - 6, de-novo AML - 2, de-novo ALL - 1) and unfit for intensive therapy. Astarabine treatment was well-tolerated. Two patients died (one from pneumonia and one from sudden death 2 weeks from end of treatment) before completing 30 days post-treatment and hence were excluded from the outcome analysis. Response to the treatment was observed in the bone marrow of 6 of the 7 newly-diagnosed patients for whom bone marrow analysis was available, 3 of whom had a continuous complete remission (CR) for 4 (ongoing), 8, and 10 months post-treatment, and 3 had a continuous partial remission (PR) for 3,7, and 7 (ongoing) months. The median overall survival (OS) of the patients with CR/PR is 7 months to date (table 1). No significant response was observed in the relapsed/refractory patients, with a median OS of 2.5 months. Twelve patients died from disease progression. Conclusions: Astarabine, a new composition of leukemia-targeted cytarabine, is safe and very well tolerated, even in patients over 80 years of age, resulting in response in 6 of 7 newly diagnosed patients with acute leukemia. To the best of our knowledge, this is the first report permitting high-dose of cytarabine, considered a cornerstone of leukemia therapy, to be given to a population of patients that heretofore did not have this option. Further dose escalation studies are currently ongoing at a cytarabine-equivalent dose of 4.5 and 6 g/m2/day. A phase II study is planned to confirm these encouraging results and define the use of Astarabine for patients otherwise unable to receive high doses of cytarabine. Disclosures Zuckerman: BioSight Ltd: Consultancy, Research Funding. Gengrinovitch:BioSight Ltd: Employment, Equity Ownership, Patents & Royalties: Inventor all of the patents. Ben-Yakar:BioSight Ltd: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of all patents.

A Double Blind Placebo-Controlled Randomized Phase III Study of High Dose Continuous Infusion Cytosine Arabinoside (araC) with or without Cloretazine® in Patients with First Relapse of Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1970-1970
Author(s):  
Francis J. Giles ◽  
Wendy Stock ◽  
Norbert Vey ◽  
Karen Seiter ◽  
Daniel J. DeAngelo ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
De Novo ◽  
Early Death ◽  
Hematologic Malignancies ◽  
Data Safety Monitoring Board ◽  
Phase Iii ◽  
High Dose ◽  
Double Blind ◽  
Phase Iii Study ◽  
First Relapse

Abstract Background: AraC is considered to be the most effective single drug in the treatment of AML. For initial treatment of AML, araC is typically administered by intravenous continuous infusion for 5–7 days at doses of 100–200 mg/m2/day, usually in combination with an anthracycline. In the relapsed setting, araC remains an option for treatment and is generally administered at higher doses either alone or in combination with other agents and in a variety of schedules. Cloretazine (VNP40101M) is a novel alkylating agent that preferentially targets the O6 position of guanine. A Phase I trial of Cloretazine with araC in advanced hematologic malignancies demonstrated significant anti-leukemic activity with minimal extramedullary toxicity (Giles et al, 2005). The purpose of the current double blind randomized Phase III study is to determine if araC with Cloretazine improves outcome in AML patients (pts) in first relapse. Methods: Eligible pts must be ≥18 years old, PS 0–2, and have AML in first relapse following a CR or CRp of 3–24 months duration. Pts are randomized using a 2:1 scheme to receive either araC 1.5 gm/m2 (d 1–3) + Cloretazine 600mg/m2 or placebo on d 2. Pts are stratified by both age and remission duration. Pts achieving CR or CRp are consolidated with araC + Cloretazine 400mg/m2, or araC + placebo according to original treatment assignment. Pts with partial response or bone marrow improvement may receive a second induction cycle. The study will accrue 420 pts, with an interim analysis for safety and efficacy at 210 pts. The primary endpoint is overall response (CR and CRp) rate. Secondary endpoints include time-to-progression, duration of response, and survival. Results: A data safety monitoring board review of the first 32 pts was performed in 12/05. Differential toxicity between the two arms was not observed. From 03/05 to 07/06, 164 pts were enrolled by 47 sites. Median age=59 yrs (range 22–83), and 52%= male. Distribution by stratum: I = 66 (<60, CR<12mos); II= 22 (<60, CR≥12mos); III= 45 (≥60, CR<12mos); IV= 31 (≥60, CR≥12mos). Blinded data are available for 110 monitored pts: 77% were de novo AML, 23% secondary AML. 107/110 pts completed the intended treatment course. The most common reported serious adverse event was infection (50%). Importantly, of 110 pts, early deaths (≤30 days from start of treatment) occurred in only 13 (12%) pts, most of which was due to infection with neutropenia, or progressive disease. Conclusions: A multi-site Phase III double-blind randomized trial for pts with AML in first relapse is feasible and demonstrates a recognized clinical need for new treatments across age and CR duration variables. The ability of pts to tolerate high-dose araC with or without Cloretazine as assessed by rate of SAE and early death is encouraging.

MO225CMV ENCEPHALITIS IN A SLE FLARE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Catarina Marouço ◽  
Dulce Carvalho ◽  
Francisco Ribeiro ◽  
Rita Magriço ◽  
Fernando Nolasco
Keyword(s):  
De Novo ◽  
Oral Prednisolone ◽  
Opportunistic Pathogen ◽  
Marrow Transplant ◽  
High Dose ◽  
High Morbidity ◽  
Solid Organ ◽  
Cmv Infection ◽  
High Doses ◽  
Screening And Prevention

Abstract Background and Aims Cytomegalovirus (CMV) infection is an opportunistic pathogen in immunocompromised patients and its management is well described after solid organ/bone marrow transplant or in HIV patients. Although less common, since Systemic Lupus Erythemathous (SLE) is a chronic auto immune disease often requiring intense immunosuppression to induce remission of disease exacerbation, SLE patients are also prone to it. Besides complicating the course of the disease, it may be a life-threatening infection. Due to the heterogeneity of SLE manifestations, usually is difficult to distinguish between a SLE flare and CMV active infection, making the diagnose challenging. It has also been described in the literature as an exacerbating SLE factor. We report the case of an Asian, 27-year-old woman, with a recent SLE diagnosis that was admitted with a SLE flare while developing a CMV encephalitis. She was previously admitted due to a nephrotic syndrome. Immunological studies revealed an ANA title of 1:640 and a positive anti dsDNA Ab with diminished C3 and C4 levels, nephrotic range proteinuria and a diagnose of SLE was made. Renal biopsy revealed class IV lupus nephritis. She started high dose intravenous methylprednisolone (3 pulses of 500mg) and mycophenolate mofetil (MMF) at a dose of 2g per day. She was discharged taking 60 mg of oral prednisolone and the same dose of MMF. Two weeks after being discharged, she was readmitted due to worsening anaemia (Hb 6.8 g/dL), thrombocytopenia (Pl 27 000/µL) and deteriorating renal function with a sCr of 5.5 mg/dL with de novo haematuria. It was admitted a severe SLE flare and she was given another 3 pulses of 500mg I.V methylprednisolone and cyclophosphamide (CYC) was started (1 pulse of 500mg I.V). At the same time, she started to complain of myalgias and malaise, generalized hypotonia, developed fever, leukopenia with neutropenia and seizures. Serum CMV viremia was 71 000 copies and CMV polymerase chain reaction was positive in cerebrospinal fluid. She was started on I.V Ganciclovir, CYC was suspended and clinical improvement was observed. Conclusion Studies about the risk of different treatment drugs and other risk factors on the development of CMV disease in SLE are lacking. These studies will be useful for establishing guidelines on the institution of prophylaxis or pre-emptive treatment of CMV infection in SLE patients. Protocols for screening and prevention in this population should be implemented to account for this emerging problem. Given the rising prevalence of CMV infection in the past few years, the authors recommend that patients recently diagnosed with SLE while taking high doses of corticosteroids, which appears to be a risk factor for CMV reactivation, should be routinely tested for CMV viremia. There should be a low threshold for suspicion, hence treatment should be started as soon as possible given the high morbidity and mortality in severe cases.

Double-Blind Study of Imipramine versus Phenelzine in Melancholias and Dysthymic Disorders

1987 ◽  
Vol 151 (5) ◽  
pp. 639-642 ◽  
Author(s):  
J. Vallejo ◽  
C. Gasto ◽  
R. Catalan ◽  
M. Salamero
Keyword(s):  
Major Depression ◽  
Blind Study ◽  
Dysthymic Disorder ◽  
Clinical Implications ◽  
High Dose ◽  
Double Blind Study ◽  
Double Blind Trial ◽  
Double Blind ◽  
Blind Trial ◽  
High Doses

In a 6-week double-blind trial, the efficacy of imipramine and high dose phenelzine were compared in the treatment of Major Depression with Melancholia, and Dysthymic Disorder (DSM-III). Both drugs were found to be equally efficacious in the treatment of 32 patients suffering from Major Depression. In 32 Dysthymic patients, phenelzine in high doses was found to be superior to imipramine. The clinical implications of these findings are discussed.

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