Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study

Cladribine is currently registered as a 10-milligram tablet formulation with a fixed cumulative dosage of 3.5 mg/kg over 2 years. It is important to investigate if an increased dosage may lead to further clinical stability with preserved safety. This study used an off-label subcutaneous (s.c.) formulation of cladribine and compared outcomes (Expanded Disability Status Scale (EDSS) scores and disease progression) between 52 relapsing multiple sclerosis (RMS) patients receiving different s.c. dosing regimens with up to 20 years of follow-up. The study group received induction therapy with s.c. cladribine (1.8 mg/kg cumulative dose; consistent with 3.5 mg/kg of cladribine tablets). Patients were subsequently offered maintenance therapy (repeated courses of 0.3 mg/kg s.c. cladribine during 5–20-year follow-up). Forty-one patients received an increased cumulative dose (higher than the induction dose of 1.8 mg/kg); 11 received the standard induction dose. Risk of progression on the EDSS correlated with lower cumulative dose (p < 0.05) and more advanced disability at treatment initiation (p < 0.05) as assessed by EDSS change between year 1 and years 5 and 10 as the last follow-up. Maintenance treatment was safe and well-tolerated, based on limited source data. Subcutaneous cladribine with increased cumulative maintenance dosage was associated with disease stability and favorable safety over a prolonged period of follow-up (up to 20 years) in RMS patients.

Impact of Age, Body Surface Area, and Body Mass Index on Pegaspargase Toxicity and Pharmacokinetics: A Report from the DFCI ALL Consortium

Introduction: Increased toxicity with pegaspargase (PEG) in older and higher body mass index (BMI) patients (pts) with acute lymphoblastic leukemia (ALL) has recently led to dose capping practices. We assessed the influence of age, body surface area (BSA), and BMI on PEG-related toxicity and pharmacokinetics from two consecutive DFCI ALL Consortium trials without dose capping. Methods: Patient (pts) aged 1 to &lt;19 years (DFCI 05-001) or 1 to &lt;22 years (DFCI 11-001) with newly diagnosed ALL were eligible for enrollment. Those who received PEG (2500 IU/m 2) were included in this analysis. Pts received 1 dose of IV PEG on day 7 of Induction and every 2 weeks for 15 doses post-induction. Serum asparaginase activity (SAA), considered therapeutic at &gt;0.1 IU/mL, was assessed 4, 11, 18, and 25 days after the Induction dose and nadir SAA was assessed before each Post-Induction dose. Asparaginase-related toxicities were prospectively assessed and graded by CTCAE version 3.0 (DFCI 05-001) or 4.0 (DFCI 11-001). Asparaginase toxicity for this analysis was defined as ≥1 of the following: pancreatitis, thrombosis, ≥grade 4 hyperbilirubinemia, ≥grade 4 hypertriglyceridemia. Allergy was analyzed separately (due to presumed dose independence). Height and weight at diagnosis were used for analyses. BMI categories were assigned using standard percentile ranges based on gender specific 2000 CDC growth charts. BSA was calculated using the Mosteller formula. Univariate analyses evaluated the relationship of age, BMI, and BSA with asparaginase toxicity. Comparisons of toxicity across BMI and BSA categories were performed using a Jonckheere-Terpstra test. Categorical comparisons for dichotomized BMI and BSA utilized a Fisher's exact test or chi square test. The relationships between BMI and BSA with toxicity were explored using multivariable models. Results: Between 4/2005-12/2011 802 pts enrolled on DFCI 05-001 and between 6/2012-6/2015 240 pts enrolled on DFCI 11-001. Both trials included random assignment of asparaginase formulation. In total 911 patients received pegaspargase during Induction and 351 during Post-Induction. During Induction, pts ≥15 years of age had higher asparaginase toxicity rates (17.1% vs 6.2%, p=0.0003) (Figure 1a). Toxicity differed significantly across BSA categories (&lt;1.5 m 2, 1.5 to &lt;2.0 m 2, ≥2.0 m 2, p= 0.007) with increased toxicity in those with BSA ≥2.0m 2 (22.7% vs. 6.8% for those &lt;2.0 m 2, p = 0.016) (Figure 1b). Age was highly correlated with BSA (Pearson r = 0.93, p &lt;0.0001). There was numerically higher toxicity in the BMI category of overweight vs. those underweight or normal weight (11.3% vs 6.5%) however this did not extend to the obese category, and overall, increasing BMI was not associated with statistically higher toxicity (p= 0.13, Figure 1c). Post-Induction, age ≥15 years was associated with increased asparaginase toxicity (57.1% vs 21%, p&lt;0.0001) (Figure 1d). Toxicity differed significantly across BSA categories (p&lt;0.0001) but was similar between BMI categories (p=0.19, Figure 1e-f). The impact of BSA was observed when dichotomized at thresholds of 1.5m 2 (54% vs. 19%, p&lt;0.0001) and 2.0m 2 (70% vs. 23%, p=0.003) (Figure 1e). Considering only those ≥10 years of age, trends for BSA/BMI and toxicity were similar. There was no significant association between BMI or BSA and allergy. In multivariable analysis, BSA was a significant predictor of Post-Induction toxicity (OR 4.21, p&lt;0.0001). Age was significant in the univariate setting (OR 1.14, p&lt;0.0001) however due to high correlation with BSA, was not included with BSA in the multivariable model. Post-Induction, median nadir SAA levels were ≥0.1IU/mL for all BSA and age categories. Median SAA was similar or lower at all time-points for those ≥15 years of age compared with younger children. Median SAA for pts with BSA ≥1.5m 2 were similar or lower compared to those with BSA &lt;1.5m 2 (Figure 2a-d). Conclusion: Age ≥15 years and BSA ≥2m 2 were each associated with significantly increased asparaginase toxicity. Older patients and those with higher BSA had similar or lower median SAA levels at all time-points. These results suggest that the differential toxicity seen in older patients and those with higher BSA is not explained by these patients having higher SAA levels. Prospective exploration of interventions to decrease toxicity in older patients and those with high BSA are needed. Figure 1 Figure 1. Disclosures Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

A Pilot Study of CPX-351 (Vyxeos ©) for Transplant Eligible, Higher Risk Patients with Myelodysplastic Syndrome

Introduction: CPX-351 (Vyxeos ©; daunorubicin and cytarabine liposome for injection) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio that is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Secondary AML is clinically and biologically similar to MDS, sharing many of the same genetic mutations. We hypothesize that CPX-351 therapy may result in deeper responses than traditional therapy with hypomethylating agents, with acceptable tolerability, and translate into better outcomes in the MDS population. This is a multicenter, dose-escalation and safety expansion study (NCT03572764) to investigate induction and consolidation therapy with CPX-351 in a transplant eligible, higher risk MDS population. Methods: Two dose levels were investigated in the dose-escalation portion. Induction Dose Level 1: (daunorubicin 29 mg/m 2 and 65 mg/m 2 cytarabine) liposome on days 1, 3, 5; and Induction Dose Level 2: (daunorubicin 44 mg/m 2 and 100 mg/m 2 cytarabine) liposome on Days 1, 3, 5. The primary objectives were to evaluate safety and to determine the dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). DLTs were assessed during the induction period (up to day 56 to evaluate for prolonged myelosuppression). Additionally, a dose expansion (for up to 20 treated patients) was performed at the RP2D. After induction, patients could receive up to two cycles of consolidation per dose level: Dose Level 1, (daunorubicin 14.3 mg/m 2 and 32 mg/m 2 cytarabine) liposome on Days 1 and 3; or Dose Level 2 (daunorubicin 29 mg/m 2 and 65 mg/m 2 cytarabine) liposome on Days 1 and 3. After induction, the patient could proceed to alloHCT at any time at the discretion of the treating physician. Key eligibility criteria included MDS patients who were naïve to hypomethylating agents, aged 18-70 years, an IPSS-R score &gt; 3 (Intermediate, High or Very High Risk), ≥ 5% bone marrow myeloblasts, and suitable candidates for cytotoxic induction therapy and allogeneic hematopoietic cell transplant (alloHCT). Key secondary endpoints were day 30 and 60 post-induction mortality, the proportion of patients proceeding to alloHCT, and response assessments per IWG 2006 criteria. Results: As of abstract submission, 19 patients have been treated and dose escalation is complete. The dose escalation portion included 12 patients (Dose Level 1, n=6; Dose Level 2, n=6), and the safety expansion to date includes 7 patients treated at Dose Level 2. The median age was 64 years (range, 18-68), 67% were female, and the IPSS-R risk categories were as follows: intermediate (n=1, 5%), high (n=10, 53%) and very high (n=8, 42%). There were no DLTs in either Dose Level 1 or Dose Level 2, and Dose Level 2 was selected for safety expansion. Treatment-emergent adverse events (TEAEs) were evaluated in the 18 patients who had completed induction (Table). The most common TEAEs were hematologic, as expected. The most common non-hematologic TEAEs were febrile neutropenia (n=13, 72.2%), hypertension (n=9, 50%), and sepsis (n=5, 27.8%). SAEs included febrile neutropenia (n=5), sepsis (n=2), lower GI hemorrhage (n=2, two instances in the same patient), atrial fibrillation (n=1), pneumonitis (n=1), and catheter related infection (n=1). To date, the 30 and 60 day mortality is 0% and 5% (n=1), respectively, with the 1 death unrelated to therapy and due to progression of disease to AML. Of the 19 patients, 13 have received alloHCT with 4 still potentially alloHCT candidates. Of response evaluable pts (n=18, 1 pt pending response evaluation at data cutoff), the overall response rate was 78% with best overall responses of CR (n=4), mCR (n=10), stable disease (n=2), progressive disease (n=2) and pending (n=1). Of the 10 patients with mCR, 3 also had hematologic improvements. Conclusions: CPX-351 (daunorubicin 44 mg/m 2 and 100 mg/m 2 cytarabine) liposome on Days 1, 3, 5, has demonstrated a tolerable safety and promising efficacy profile when used in a transplant eligible, higher risk MDS population, warranting further study. Updated safety and efficacy outcomes will be presented at the meeting. Figure 1 Figure 1. Disclosures Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Komrokji: AbbVie: Consultancy; Acceleron: Consultancy; Geron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Uy: AbbVie: Consultancy; Macrogenics: Research Funding; Agios: Consultancy; GlaxoSmithKline: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Astellas: Honoraria, Speakers Bureau; Jazz: Consultancy. OffLabel Disclosure: CPX-351 (Vyxeos©; daunorubicin and cytarabine liposome for injection) is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes

THE DIFFERENT TIMING OF ORAL CLONIDINE PREMEDICATION EFFECT ON SEDATION SCORE IN SPINE SURGERY

Background: Premedication is the administration of medication before anaesthesia. It is used to prepare the patient for anaesthesia and to provideoptimal conditions for surgery. Methods: The study of oral premedication dose of clonidine in spinal surgery at different time was conducted on sixty ASA grade-1 patients of eithersex between 20 to 60 years of age undergoing elective spine surgery. This study was performed after approval from ethics committee of the institute.Informed consent was obtained from each patient. Results: The total induction dose of propofol required for the induction of the patient is 2-2.5 mg/kg body weight. In our study the average weightof the patient in group-1 was 58.83 kg and in group-2, average weight of the patient was 54.77 kg. The total average weight of patient in the study was 56.80 kg. Thus the total induction dose of propofol required should have been 117.66 mg in group-1, 109.54 mg in group-2 and 113.6 mg in averagetotal. Conclusion: In conclusion this study establishes that the premedication with tab. clonidine 200µg (As tab. clonidine is available in 100µg) 90 minutebefore the surgery or 3.5 hour before the surgery reduced induction dose of propofol. Keywords: Clonidine, Propofol, Spine

Use of priming principle in the induction dose requirement of propofol and its hemodynamic stability- A cross sectional study

In anesthesia propofol induction is administered at a dose of 2mg/kg as a single bolus and when given at this dose the commonest problem faced by the anesthetist is the sudden drop in the blood pressure, as the hypotensive effect of propofol is proportional to the dose and rate of administration.To study the effect of auto co-induction (priming principle) in the requirement of induction dose of propofol and the resulting hemodynamic parameters. A prospective randomized double blinded study was conducted for a period of one year in the department of anesthesia at a government medical college hospital in TamilNadu. A total of 60 patients were selected for our study and were randomly allocated into two groups of 30 each. Group A is the study group (priming) and group B is the control group (non-priming group). In the priming group, three minutes after premedication the co induction agent was administered (25% of the calculated dose of propofol) and two minutes later the patient received propofol at a rate of 30mg/10 sec until loss of vocalization was achieved. The hemodynamic parameters along with the total dose requirement of propofol and BIS values were monitored at regular intervals after induction.The mean total dose of propofol required among the priming group patients was 78.2 mg compared to the total dose requirement in the non-priming group which was 92.5 mg and the mean difference was found to be statistically significant. A statistically significant fall in the heart rate and blood pressure was observed at 1 min and 3 mins after induction in non priming group compared to priming group. By applying priming principle the induction dose of propofol was reduced by 14.25% with a good hemodynamic stability.

COMPARISON OF TWO DIFFERENT DOSES OF ORAL MIDAZOLAM PREMEDICATION ON INDUCTION DOSE AND CHARACTERISTICS OF PROPOFOL: A DOUBLE BLIND STUDY

Background: Midazolam is a water-soluble, short acting benzodiazepine. The objective of our study was to study the effect of two different doses of oral midazolam premedication on propofol induction dose and characteristics. Methods: Randomized, prospective, double blind study conducted on 100 ASA I and II patients, falling between the age group of 18-60 yrs were randomly divided in to two groups, group I and group II, who received 7.5mg and 15mg midazolam orally 45 mins before the surgery respectively. Results: Mean time taken for induction in group-A was significantly higher in group-I as compare to group-II. No significant difference was noted with respect to degree of sedation, changes in the heart rate and means arterial pressure, oxygen saturation between the two groups. Conclusion: Our study concluded that 15mg midazolam premedication offers more benefits than 7.5mg midazolam by reducing induction dose of propofol without any undesirable effects like excess sedation, bradycardia and hypotension. Keywords: Midazolam, Induction, Premedication