Cytoprotective Palifermin Allowed Melphalan Dose Escalation to 280mg/2 for Multiple Myeloma Patients with Normal Renal Function Receiving Autologous Stem Cell Transplantation (ASCT) - Final Results of a Phase 1 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2401-2401
Author(s):  
Muneer H. Abidi ◽  
Nishant Tageja ◽  
Lawrence G. Lum ◽  
Judith Abrams ◽  
Zaid Al-Kadhimi ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Actual Body ◽  
Median Duration ◽  
Dose Escalation ◽  
Normal Renal Function ◽  
Dose Effect ◽  
Actual Body Weight ◽  
Cd34 Cells ◽  
Grade 3

Abstract Abstract 2401 Background: Melphalan (M) 200 mg/m2 is a standard conditioning regimen for myeloma patients (pts) with normal renal function (NRF) undergoing ASCT. M exhibits a steep, log-linear dose effect with a potential for dose escalation (DE) to overcome M resistance. However, severe oral mucositis (OM) at M ≥ 200 mg/m2 precludes DE due to significant morbidity. Palifermin (P) as a cytoprotective agent has demonstrated efficacy in reducing intensity and duration of OM in pts receiving intensive chemo-radiotherapy. We designed a phase I study to determine the MTD of M in pts with NRF when used with P. Study Design: We enrolled 19 pts from 07/2007 to 09/2009. Data is reported on 18 evaluable pts as 1 pt was removed due to the inability to receive all 6 doses of P. DE was done (3 pt cohorts) in 20 mg/m2 increments, depending on the dose limiting toxicities (DLT). Level (L) 1 began at M 200 mg/m2 with P 60 mcg/kg/d, given as I.V. bolus on Day -5, -4, -3 and Day +1, +2 and +3 (PBSCs infused on Day 0). M was given on D-2 up to and including 280 mg/m2 (n = 6). If no symptomatic grade ≥ 3 DLTs were noted by day +30, an additional cohort of 3 pts were entered at the next dose level. Dose escalations were to stop if ≥ 2 DLTs occurred at M dose; with that dose declared as the MTD. Grade 3/ 4 diarrhea and ≥ grade 3 cardiac toxicity was considered DLT; grade 3/4 hematological toxicity was acceptable. The grade of OM was assessed daily according to the WHO oral-toxicity scale (grade 0–4). Key Eligibility Criteria: age 18–74 years, stage 2/3, ECOG performance status < 2, CrCl > 60, total bilirubin ≤ 1.5 × IULN, ALT/AST ≤ 3 × IULN, eligible for ASCT per institutional criteria and at least 2.0 × 106 CD34+ cells/kg cryopreserved for ASCT. Calculation of M dose: M dose was calculated using the actual body weight except when the actual body weight was > 40% above the ideal body weight; in that case, adjusted body weight was used. Results: Med age 48.5 y (33-65). Med # of prior Rx: 2 (1-5). Median CD34 cells dose 4.77 × 10(6) [2.18-11.36]; median day of neutrophil recovery +10 (10-13) and median day of platelet engraftment 19.5 (0 to 29). The overall incidence of OM ≥ grade 3 was 44% (8/18) with a median duration of OM 10 days (4 -20 d). Only 1 pt in L 1 group developed grade 4 OM. Two out of 6 pts given M 280 mg/m2 did not develop any OM. Atrial fibrillation occurred in 1/6 pts treated with M 280 mg/m2. The most common adverse events included rash (18 events, no grade 3), elevation of amylase (10, 4 grade 3-asymptomatic) and lipase (5, 2 grade 3 -asymptomatic) and edema (11, no grade 3). 11 pts (61%) required IV opioid analgesics; none needed TPN/NG feeding. All 18 pts were evaluable for response at D+100 and there were no treatment-related deaths. Median duration of follow up is 17.5 months (5.6-36.5). At D+100, all 18 patients were progression free. At D+365, 13 pts are free of progression, 2 have PD, and 2 have expired while 1 pt has not reached D+ 365 yet. First expired pt on L5 relapsed at 5 months post ASCT and no further details are available on two other expired patient. Conclusions: Palifermin permits dose escalation of M up to 280 mg/m2 with acceptable toxicity. A phase 2 trial is planned to better delineate the anti-myeloma efficacy of this regimen. Disclosures: Abidi: Millennium: Speakers Bureau. Off Label Use: Bortezomib is currently not approved for maintenance therapy after Autologous stem cells transplant. Lum: Transtarget Inc: Equity Ownership.

scholarly journals Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Visanu Thamlikitkul ◽  
Yanina Dubrovskaya ◽  
Pooja Manchandani ◽  
Thundon Ngamprasertchai ◽  
Adhiratha Boonyasiri ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Steady State ◽  
Renal Insufficiency ◽  
Actual Body ◽  
Normal Renal Function ◽  
Polymyxin B ◽  
Poor Correlation ◽  
Actual Body Weight ◽  
Significant Difference

ABSTRACT Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CLCR] ≥ 80 ml/min) at baseline, whereas 14 had renal insufficiency (CLCR < 80 ml/min). The mean AUC of polymyxin B ± the standard deviation in the normal renal function cohort was 63.5 ± 16.6 mg·h/liter compared to 56.0 ± 17.5 mg·h/liter in the renal insufficiency cohort (P = 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 ± 7.0 mg·h/liter versus 29.7 ± 11.2 mg·h/liter, P = 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.

Impact of Increased Body Weight on Acute Toxicity and Outcome of Autologous Stem Cell Transplantation for Non-Hodgkin’s Lymphoma: A Southwest Oncology Group Analysis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 352-352 ◽  
Author(s):  
Patrick Stiff ◽  
Joseph Unger ◽  
Stephen Forman ◽  
Michael LeBlanc ◽  
Thomas Miller ◽  
...  
Keyword(s):  
Body Weight ◽  
Stem Cell ◽  
Actual Body ◽  
Death Rate ◽  
Skin Toxicity ◽  
High Dose ◽  
Cell Transplant ◽  
Actual Body Weight ◽  
Grade 5 ◽  
Grade 3

Abstract Little is known about the optimal dosing of chemotherapy agents in patients significantly above their ideal body weight (IBW) who undergo high dose therapy with an autologous or allogeneic hematopoietic stem cell transplant. While dose attenuation is often advocated for overweight patients and appears to reduce acute toxicities, its effect on progression-free and overall survival (PFS/OS) is unknown. Due to a high relapse rate after autografts for relapsed/refractory NHL, SWOG has long investigated the use of augmented preparative regimens that utilize high-dose etoposide based on actual body weight (ABW) of 60 mg/kg, along with 12 Gy of TBI and cyclophosphamide (100 mg/kg) which is dosed on unadjusted IBW. We determined acute toxicities and PFS/OS using this approach in a recently completed study (S9438) of 358 patients undergoing autografts for relapsed/refractory NHL, comparing all grade 5 toxicities, grade 3–4 skin toxicities (known to be associated with high dose etoposide) and all other grade 4 toxicities in patients in this study based on % above IBW. The Devine formula for IBW with an adjustment for patients <5 feet was used. Patients at or below their IBW were dosed using their actual body weight. All patients received the preparative regimen as stated followed by autologous peripheral blood stem cells. Overall there were 31 patients with grade 5 toxicities. This group was a mean 42% above their IBW vs 24% for those surviving transplant (p=.001). Increasing % above IBW predicted grade 5 toxicity (p=.002). Even those at or 10% above their IBW had a higher toxic death rate (10.1 vs 3.6%; p=.04). While increasing weight above IBW did not predict for grade 4 lung, liver, cardiac toxicities or infections (p=.12), it did predict for grade 3/4 skin toxicities (p< .001). Skin toxicity, most commonly hand/foot syndrome was seen at rates up to 27.3% vs 7.3% for those ≥ 50 vs < 50% over IBW (p < .001). However, even those just ≥ 10% over IBW had nearly a 4 fold higher risk of skin toxicity (13.4 vs 3.6%; p=.005). While survival by % over IBW is confounded by comorbidities in overweight patients, we found no evidence of a different 2-year PFS or OS for overweight patients, even those ≥ 50% above IBW (PFS=42 vs 45%, p = .28; OS=52 vs 62%, p = .38). These multicenter trial data do establish a correlation of the ABW dosing of etoposide with significant skin toxicity. Without an apparent later PFS/OS benefit to the use of unadjusted etoposide dosing for overweight patients but higher acute skin toxicity and a higher early death rate, etoposide will be dosed using adjusted IBW [ IBW + .4 (ABW − IBW)] in subsequent studies of this regimen.

scholarly journals Effects of Obesity on the Efficacy and Toxicity of Induction Chemotherapy in Adult Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1290-1290
Author(s):  
Tim J Peterson ◽  
Andrew Lin ◽  
Patrick Hilden ◽  
Sean Devlin ◽  
Nelly G. Adel ◽  
...  
Keyword(s):  
Body Weight ◽  
Actual Body ◽  
Induction Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
Performance Status ◽  
Retrospective Chart Review ◽  
Obese Patients ◽  
Actual Body Weight ◽  
Obese Adults ◽  
Grade 3

Abstract Background The efficacy and toxicity of induction regimens for acute lymphoblastic leukemia (ALL) are affected by numerous patient and regimen specific variables including age, performance status, cytogenetics, comorbidities, and the selection and dosing of chemotherapeutic agents. Notably, the incidence of leukemia and the ability to achieve remission have been shown to be affected by obesity.1,2 Although there is a lack of data in obese adults with ALL, previous studies have confirmed the poor prognostic implications of obesity in pediatric patients.3 Current practice with regard to chemotherapy dosing in obese patients is dependent on the American Society of Clinical Oncology (ASCO) guidelines, which recommend that chemotherapy should be dosed on actual body weight, regardless of obesity status.4 With the lack of data in obese adults with ALL, it has been postulated that empirically reducing chemotherapy doses may worsen their prognosis. This provided the rationale for this investigation into the effect of obesity on the efficacy and toxicity of induction chemotherapy in adults with ALL. Methods The primary objective of this study was to evaluate complete remission (CR) rate to initial induction chemotherapy of obese patients (defined as actual body weight (ABW) > 130% of ideal body weight (IBW)), compared to that of non-obese patients. Secondary objectives included overall survival (OS), relapse free survival (RFS), time to platelet and absolute neutrophil count (ANC) recovery, and grade 3/4 non-hematologic toxicities as graded by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). OS and RFS were estimated by the Kaplan-Meier method, with differences across groups accessed via the logrank test. The incidence of CR was estimated by the cumulative incidence method for competing risks, with differences across groups accessed via Gray's test. Death was considered a competing risk for CR. This retrospective chart review included patients with ALL who received initial induction chemotherapy between January 1, 2003, and December 31, 2013, at Memorial Sloan Kettering Cancer Center (MSKCC). Patients included were > 18 years old, newly diagnosed with ALL who were chemotherapy-naïve for treatment of ALL. Results Seventy-two patients were identified during the specified period with a median age at diagnosis for all patients of 46 years (18-86). Patients were primarily excluded as chemotherapy was initiated prior to establishing care with MSKCC. A majority of patients received multi-agent chemotherapy with ALL2, L-20, NY-II, ECOG2993, and CALGB 10403 with a smaller subset of patients of older age or poor performance status treated with vincristine and steroids. Twenty-three patients were identified as being obese with a median of 154% of their IBW. The median % of IBW among the non-obese patients (49 patients) was 115%. All patients received chemotherapy based on body surface area (BSA) calculated on total body weight. All patients in the obese group and 96% of non-obese patients experienced at least one grade 3 or 4 non-hematologic toxicity. Time to ANC recovery (26 days vs. 31 days, for obese and non-obese patients respectively) and platelet recovery (29 days vs. 35 days, respectively) were not different between groups. There was no difference in the cumulative incidence of CR among obese and non-obese patients (p=0.477), with a 1 year incidence of 96% in both groups. RFS was similar among obese and non-obese patients (p=0.203, 36.4% and 52.9% respectively at 3 years). Similarly, there was no significant difference in OS between obese and non-obese patients (p=0.161, 45.5% and 57.1% respectively at 3 years). Univariate analyses demonstrated that there was no significant effect of intensity of regimen utilized or baseline cytogenetics on relapse free survival or overall survival. Conclusion The findings of this retrospective chart review are consistent with current ASCO guidelines for dosing in obese patients. As there were no differences noted in efficacy or safety between obese and non-obese patients in our study, it remains appropriate to continue dosing obese patients based on actual body weight. Further prospective evaluations are necessary to confirm these findings. References Pulte et al. PloS ONE 2014; 9: e85554. Castillo JJ et al. Leuk Res 2012; 36:868-875. Butturini AM et al. Journ Clin Onc 2007; 25(15):2063-2069. Griggs JJ et al. J Clin Oncol 2012; 30(13): 1553-61. Disclosures No relevant conflicts of interest to declare.

Toxicity of chemotherapy dosing using actual body weight in obese versus normal-weight patients: A systematic review and meta-analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6013-6013
Author(s):  
Kathryn Cunningham Hourdequin ◽  
William Lewis Schpero ◽  
Breanne Lee Piazik ◽  
Dorothy R McKenna ◽  
Robin Joyce Larson
Keyword(s):  
Systematic Review ◽  
Body Weight ◽  
Actual Body ◽  
Meta Analysis ◽  
Normal Weight ◽  
Cochrane Library ◽  
Hematologic Toxicity ◽  
Obese Patients ◽  
Actual Body Weight ◽  
Grade 3

6013 Background: Because weight-based chemotherapy calculations can be very large in obese patients, oncologists often empirically reduce doses due to fear of excess toxicity. The resulting underdosing may negatively impact survival. We performed a systematic review and meta-analysis to determine whether, among adults receiving chemotherapy dosed by actual body weight (ABW), obese patients experience differing toxicity or survival compared to normal-weight patients. Methods: We searched MEDLINE, Cochrane Library, Web of Science, and ClinicalTrials.gov through October 2011 and reviewed reference lists. We included studies that compared outcomes of obese versus normal-weight adults receiving chemotherapy dosed according to ABW (+/- 5% variability). Studies followed subjects for at least one cycle of chemotherapy and reported at least one pre-specified outcome. Two authors independently abstracted data from eligible studies. We used random effects models to pool odds ratios (OR) for hematologic and non-hematologic toxicities. We summarized survival qualitatively. Results: Of 3,921 studies, five met inclusion criteria, for a total of 6,877 subjects. Based on three studies, Grade 3/4 hematologic toxicity occurred less often in obese patients than normal-weight patients (OR 0.68, 95% CI 0.51-0.89, I2=29%). A fourth study comparing leukocyte nadirs had variable results depending on the regimen, dosing, and patient co-morbidities. Based on two studies, Grade 3/4 non-hematologic toxicity occurred less often in obese patients than normal-weight patients (OR 0.74, 95% CI 0.63-0.87, I2=0%). A third study found rates of infection did not significantly differ. Three of four studies reported reduced overall survival in obese patients (statistical significance not reported). Conclusions: Contrary to common belief, obese patients receiving chemotherapy based on ABW appear to have lower rates of both hematologic and non-hematologic toxicities compared to normal-weight patients. These results do not support the practice of empiric dose reduction in obese patients. Further research should explore etiologies for the reduced survival in this group.

Adjusted versus actual body weight dosing of 4-factor prothrombin complex concentrate in obese patients with warfarin-associated major bleeding

2018 ◽  
Vol 47 (3) ◽  
pp. 369-374 ◽  
Author(s):  
Keaton S. Smetana ◽  
Rachel Ziemba ◽  
Casey C. May ◽  
Michael J. Erdman ◽  
Edward T. Van Matre ◽  
...  
Keyword(s):  
Body Weight ◽  
Actual Body ◽  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Obese Patients ◽  
Actual Body Weight

scholarly journals Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

2018 ◽  
Vol 63 (2) ◽  
pp. e01957-18 ◽  
Author(s):  
Anne B. Leuppi-Taegtmeyer ◽  
Laurent Decosterd ◽  
Michael Osthoff ◽  
Nicolas J. Mueller ◽  
Thierry Buclin ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Normal Renal Function ◽  
Maintenance Dose ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Optimal Dosing ◽  
Colistimethate Sodium

ABSTRACT Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60 kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5 mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8 h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.)

scholarly journals Actual body weight-based vancomycin dosing in neonates

2019 ◽  
Vol 31 (6) ◽  
pp. 307-312 ◽  
Author(s):  
Pavla Pokorná ◽  
Martin Šíma ◽  
Olga Černá ◽  
Karel Allegaert ◽  
Dick Tibboel ◽  
...  
Keyword(s):  
Body Weight ◽  
Actual Body ◽  
Actual Body Weight

Unfractionated heparin infusion for treatment of venous thromboembolism based on actual body weight without dose capping

2019 ◽  
Vol 25 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Julia A Shlensky ◽  
Kristina M Thurber ◽  
John G O’Meara ◽  
Narith N Ou ◽  
Jennifer L Osborn ◽  
...  
Keyword(s):  
Body Weight ◽  
Venous Thromboembolism ◽  
Actual Body ◽  
Unfractionated Heparin ◽  
Obese Group ◽  
Morbidly Obese ◽  
Actual Body Weight ◽  
Bleeding Events ◽  
Heparin Infusion ◽  
Significant Difference

Controversy exists regarding the use of dose capping of weight-based unfractionated heparin (UFH) infusions in obese and morbidly obese patients. The primary objective of this study was to compare time to first therapeutic activated partial thromboplastin time (aPTT) in hospitalized patients receiving UFH for acute venous thromboembolism (VTE) among three body mass index (BMI) cohorts: non-obese (< 30 kg/m2), obese (30–39.9 kg/m2), and morbidly obese (⩾ 40 kg/m2). In this single-center, retrospective cohort study, patients were included if they ⩾ 18 years of age, had a documented VTE, and were on an infusion of UFH for at least 24 hours. Weight-based UFH doses were calculated using actual body weight. A total of 423 patients met the inclusion criteria, with 230 (54.4%), 146 (34.5%), and 47 (11.1%) patients in the non-obese, obese, and morbidly obese cohorts, respectively. Median times to therapeutic aPTT were 16.4, 16.6, and 17.1 hours in each cohort. Within 24 hours, the cumulative incidence rates for therapeutic aPTT were 70.7% for the non-obese group, 69.9% for the obese group, and 61.7% for the morbidly obese group (obese vs non-obese: HR = 1.02, 95% CI: 0.82–1.26, p = 0.88; morbidly obese vs non-obese: HR = 0.87, 95% CI: 0.62–1.21, p = 0.41). There was no significant difference in major bleeding events between BMI groups (obese vs non-obese, p = 0.91; morbidly obese vs non-obese, p = 0.98). Based on our study, heparin dosing based on actual body weight without a dose cap is safe and effective.

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