Dalteparin in Newborn Thrombosis, Time for a New Starting Dose

Background: Neonatal thrombosis is a frequently encountered complication in a neonatal intensive care unit. Dalteparin can be used to treat thrombosis in newborn infants. Objectives: In this study, we evaluate the current recommended starting dose of 129 ± 43 U/kg/24 h, hypothesizing that this dose is too low to reach therapeutic anti-Xa levels. Methods: From 2008 until 2017, all infants treated with dalteparin in the University Medical Centre Utrecht were included in this study. In this retrospective cohort study, the correlation between dose and anti-Xa level was observed. Results: Sixty-six infants were included. The most common thrombus types were catheter-related (29 patients, 44%) and venous sinus thrombosis (28 patients, 43%). The mean dalteparin dose needed for the first adequate anti-Xa level (0.5–1.0 IU/mL) was 297.6 U/kg/12 h. Two infants developed a first bleeding episode under dalteparin therapy; they both had anti-Xa levels in the therapeutic range. Conclusion: The increase of the starting dose of dalteparin will lead to earlier therapeutic levels of anti-Xa in the studied population and appears to be safe. However, this needs to be evaluated in further study.

Impact of dose reductions on clinical outcomes among patients (pts) with metastatic pancreatic cancer (mPC) treated with liposomal irinotecan (nal-IRI) in oncology clinics in the United States.

665 Background: The recommended starting dose for nal-IRI is 70mg/m2 (free base, equivalent to 80 mg/m2 salt-based dosing). This study evaluates the impact of nal-IRI dose reductions on clinical outcomes. Methods: Using the nationwide Flatiron Health electronic health record-derived database, de-identified data were extracted and analyzed for adult mPC pts treated with nal-IRI Jan 2014-Jan 2019 and who initiated treatment at approximately the recommended dose (RD), 70mg/m2 +/- 5mg. Initial dose was derived from structured medication records, prioritizing administrations. The cumulative dose (CD) of nal-IRI over the first six weeks of treatment, the presence of dose reductions (DR) – (a decrease ≥ 7mg/m2), overall survival (OS) from treatment initiation, and duration of treatment (DoT) were assessed. Results: 257 mPC pts treated with nal-IRI (median age: 68y, IQR: 61 - 73) were identified initiating therapy at approximately the RD. 26.5% (N = 68) of pts experienced a DR during treatment. Mean 6-week CD was 175.8 mg/m2 (SD: 77.9) among pts with no DR. For pts with DR, mean CD was 191.8 mg/m2 (53.2). Median DoT was 6.1 wks (IQR: 2.1 – 15.3). Pts that experienced a DR had a longer median DoT: 15.1 wks (7.1 – 23.0) vs 4.3. wks (2.1 – 12.1) for pts with no DR. Overall Median OS (mOS) was 4.2 months (95% CI: 3.7 – 5.4). mOS for DR pts was 7.2 mos (95% CI: 5.5 – 9.7) and 3.7 mos (3.0 – 4.1) for pts who did not experience a DR. Conclusions: This real-world analysis suggests that reducing the dose of subsequent administrations of nal-IRI during treatment is associated with pts remaining on therapy longer, experiencing a larger CD, and a with longer OS. Additional real-world prospective studies are necessary to characterize the impact of nal-IRI dosing on clinical outcomes.

Does initial dosing of levothyroxine in infants with congenital hypothyroidism lead to frequent dose adjustments secondary to iatrogenic hyperthyroidism on follow-up?

Background: Congenital hypothyroidism (CH) is the most common preventable cause of intellectual disability. The recommended starting dose of levothyroxine (LT4) is between 10 and 15 μg/kg, an extremely wide range. We hypothesized that a sizable proportion of newborns treated for CH at the higher end of the dosage range become biochemically hyperthyroid at a follow-up visit. Methods: This study is a retrospective chart review of infants with CH between 2002 and 2012. Results: Of the 104 patients included in this analysis, the average age at diagnosis was 11 days and the average starting dose of LT4 was 12±2.5 μg/kg. At follow-up, 36.5% required a dose reduction because of iatrogenic hyperthyroxinemia, 51% required no dose adjustment and 12.5% required a dose increase due to an elevated thyroid stimulating hormone (TSH). The starting doses of LT4 for those requiring a dose reduction, those not requiring an adjustment and those requiring an increase in the dose were 13.2±2.4, 11.5±2.1 and 10.3±2.6 μg/kg/day, respectively (p≤0.0001). Of the 34% of infants treated with an initial dose of >12.5 μg/day, 57.1% required a dose reduction at follow-up, compared to 26.1% of those whose initial starting dose was ≤12.5 μg/kg/day (p=0.007). Conclusions: Following the guidelines for initiating therapy for CH, 36.5% of the infants required a dose reduction for iatrogenic hyperthyroxinemia. These infants received a higher dose of LT4 than the infants who either required no adjustment or required an increase in the dose. A narrower range for initial dosing in CH may be appropriate.

Dose escalation of cabozantinib as a viable option for the treatment of mRCC.

636 Background: Cabozantinib (C) is a tyrosin kinase inhibitor (TKI) specific for VEGFR, MET and AXL. The phase-3 registration trial METEOR showed that C significantly improved progression-free and overall survival compared to Everolimus in patients with advanced/metastatic renal cell carcinoma (RCC) after failure of at least one VEGFR TKI and C was granted approval. In METEOR, starting dose for C was 60 mg once daily and dose de-escalation to 40 or 20 mg or stopping of C was done based on toxicity. The median dose was 43 mg. The dose had to be reduced in 62% of patients. By packing insert of C the recommended starting dose is 60 mg. We assumed that starting with 40 mg of C and escalating to 60 mg after getting accustomed to side effects may lead to a higher median dose of C. Methods: We report 20 RCC patients all started with C 40 mg and escalated to 60 mg when possible. We calculated the median time on therapy and the median dose and determined the best response. Results: The median time on C was 77 days for the patients having stopped therapy (n = 9). The median dose of C for the whole cohort was 46.0 mg. For the patients still on therapy (n = 11), the median dose was 47.7 mg. Eleven (55%) patients could be escalated to 60 mg (10 (91%) remained on 60 mg) and only 5 (25%) of patients had to be de-escalated to 20 mg. C did not have to be stopped due to toxicity. For best response, 47% reached partial remission, 13% stable and 40% progressive disease. Conclusions: Starting with 40 mg of C and escalating to 60 mg when possible may lead to a higher median dose of C compared to standard vice versa and seems to achieve responses comparable with the METEOR trial. These findings are limited by the small number of patients but warrant a prospective trial directly comparing both the escalating and de-escalating dosing schemes.

Can individualized sunitinib dose and schedule changes optimize outcomes for kidney cancer patients?

The recommended starting dose and schedule for sunitinib is 50 mg daily for 28 days, followed by a 14-day break with significant dose reductions to 37.5 mg (75% of starting dose), and then 25 mg (50% of starting dose) on the same schedule (four/two schedule). There are several reasons why these dose and scheduling recommendations may not be optimal for most patients, as outlined below.

Experience with Long-Term Lenalidomide (LEN) Treatment in the Clinical Setting: Results From the UK Revlimid® Treatment Continuation Scheme™ (TCS)

Abstract 4067 Background: Existing evidence has shown that continuing treatment with LEN plus dexamethasone (LEN-DEX) until disease progression in responding patients (pts) with relapsed/refractory multiple myeloma (RRMM) is associated with improved survival. In accordance with National Institute of Clinical Excellence (NICE) guidelines, LEN-DEX is reimbursed for treatment of RRMM pts after ≥2 therapies in England and Wales (current license after ≥1 prior therapy). The TCS database was designed as part of the NICE agreed pt access scheme, to track the duration of treatment for RRMM pts prescribed LEN-DEX. This scheme was not designed to record reasons for dose adjustments or treatment discontinuation. We studied LEN starting dose, dose modifications, and duration of treatment (in an anonymized dataset generated for statistical analysis). Methods: This prospective cohort analysis focused on pts enrolled in the TCS program between 1 July 2009 and 1 May 2010, to allow pts to be followed up for at least 2 years, unless they discontinued treatment earlier. The cut-off date was 30 June 2012. Associations between ordered categorical variables were measured by Spearman's rank correlation or Pearson's correlation for continuous variables. Baseline covariates (age and starting dose) were modeled using multivariable logistic regression with possible interactions considered. Statistical significance was considered at the 5% significance level. Results: A total of 1,286 pts with RRMM from 185 UK treatment centers were evaluable. The median age was 69 yrs (range, 34–91); 427 pts were aged <65 yrs (33%), 529 pts were aged 65–74 yrs (41%), and 330 pts were aged >75 yrs (26%). Majority of pts (n = 835; 65%) initiated LEN treatment according to the recommended starting dose of 25 mg/d; 180 (14%) pts started at 15 mg, 212 (16%) at 10 mg, and 59 (5%) at 5 mg. Dose modifications were reported in 50% of pts, and the median number of changes in dose per subject was 1 (range, 0–15). The greatest percentage of dose modifications per cycle occurred in pts with the lowest starting dose (5 mg). A total of 340 (45%) pts who started on 25 mg/d and received >1 cycle required no dose adjustments. There was a relationship between dose adjustment and duration of treatment; pts without an adjustment received an average of 9.1 cycles while those with at least one form of adjustment received 14.3 cycles (P < 0.001). The median number of cycles administered was 7 (range, 1–38), similar to that seen in LEN clinical trials (median 9.2 mos in pts with ≥2 prior therapies); 456 (35%) pts remained on therapy for ≥12 cycles and 201 (16%) pts remained on therapy for ≥24 cycles. Six percent of all pts receiving ≥24 cycles had dose modifications directly after cycle 1, with the percentage of dose modifications steadily decreasing from cycle 6 onwards. There was a positive association between a higher starting dose and longer treatment duration (P < 0.001). Of the pts who started on 25 mg/d and ≤10 mg/d, 18% and 9% received ≥24 cycles, respectively. There was a significant negative correlation between age and the number of cycles administered (P = 0.018): of the pts aged <75 yrs, 17% received ≥24 cycles; pts ≥75 yrs, 11% received ≥24 cycles. Multivariate analyses were carried out to evaluate predictors for treatment duration. Age and starting dose were both found to be statistically significant predictors for a treatment duration lasting ≥24 mos: pts aged <65 yrs and 65–74 yrs were 1.61 times (P = 0.030) and 1.65 times (P = 0.019) more likely to have a duration >24 mos compared with pts ≥75 years, respectively. Pts were 2 times (P = 0.010) more likely to achieve ≥24 cycles if receiving 25 mg as their starting compared with those starting on 10 mg/d. Conclusions: Results of this “real-world” clinical analysis support 25 mg LEN as an optimal starting dose for the majority of RRMM pts. A positive correlation between the recommended starting dose and longer treatment duration was observed. In addition, individual dose adjustments of LEN during therapy appeared to be associated with extended treatment duration in this setting. Disclosures: Williams: Celgene, Janssen-Cilag: Honoraria. Simcock:Celgene: Employment. Lodhi:Celgene: Employment. Robinson:Celgene: Employment. Davies:Celgene, Johnson & Johnson, Onyx, Novartis: Honoraria, Speakers Bureau; Merck: Speakers Bureau.