Primecuts – This Week In The Journals

October 5, 2015

seaturtlenestingpark7172380387_t755_h711f6407b865205a7bc3fa39528a0c8fdae7993dOlivia Begasse de Dhaem, MD

Peer Reviewed  

Last month, Turing Pharmaceutical bought the rights to pyrimethamine, also known as Daraprim, and subsequently raised its price significantly (from $13.5 to $750 per tablet). Unlike Rodelis Therapeutics who gave back cycloserine when facing resistance, Turing Pharmaceuticals are determined to keep their newly increased price for Daraprim.[1] The new trend in the pharmaceutical world of acquiring old medications and increasing their prices has led to controversy on whether the government should take action in regulating pharmaceutical prices and where the burden of financing pharmaceutical research should be placed.[2] 

Is doxyrubicin needed as part of adjuvant chemotherapy for Wilms Tumor? 

Wilms Tumor, a common childhood tumor, is a treatable malignancy with an excellent prognosis. Current standard of care includes surgical resection and adjuvant chemotherapy with a regimen including doxorubicin. The increased survival with this treatment modality has raised concerns about the long term effects of cardiotoxicity with doxorubicin. This week in The Lancet, a randomized controlled trial[3] was published addressing the question of whether a post-operative chemotherapeutic regimen without doxorubicin was non-inferior to the current standard post-operative chemotherapeutic regimen. The trial enrolled 583 patients with histologically intermediate risk stage II-III Wilms’ tumors and randomized them to post-nephrectomy chemotherapy with standard therapy (vincristine, actinomycin D, and doxorubicin) or a doxorubicin free regimen. The primary outcome, 2-year event-free survival difference, was 4.4%, which is less than the preset 10% non-inferiority margin. There were no significant differences in 5-year event-free and overall survival between the two groups. In conclusion, a post-operative chemotherapy regimen without doxorubicin is non-inferior to standard doxorubicin containing post-op chemotherapy in select stage II-III Wilms’ tumor patients with intermediate risk histology. This suggests that patients with select stage Wilms’ tumor can be spared the risk of cardiotoxicity of doxorubicin treatment without compromising long term survival outcomes.

Ankylosing Spondylitis (AS) is associated with an increased risk of cardiovascular and cerebrovascular mortality in men. 

Ankylosing Spondylitis is a chronic inflammatory arthritic disease of relatively young people mostly affecting the spine. Chronic inflammation is associated with accelerated atherosclerosis, endothelial dysfunction, and resultant increased risk of cardiovascular morbidity.

The Annals of Internal Medicine published a Canadian population-based retrospective cohort study[4] that used health administrative data to study the association between ankylosing spondylitis and cardiovascular and cerebrovascular mortality. 21,473 Ontarians diagnosed with ankylosing spondylitis were matched with 86,606 controls by age, sex, and region. Patients with baseline coronary artery disease and/or cerebrovascular disease were excluded. The results were adjusted for a history of diabetes, hypertension, peripheral vascular disease, cancer, dementia, chronic kidney disease, inflammatory bowel disease, and relevant medications. The primary outcome was defined as vascular mortality, which is combined cardiovascular and cerebrovascular mortality. The vascular mortality rate was 1.02 per 1000 person-years for the AS patients vs. 0.87 per 1000 person-years for the controls, which gives an adjusted hazard ratio was 1.36 (95% CI, 1.13 to 1.65). However, when adjusting for sex on subgroup analysis, the increased vascular mortality in the AS group was only observed for men. This is congruent with the observation that women with AS tend to have lower CRP levels and lower rates of MRI positivity than men with AS. This study demonstrates that patients, specifically male patients, with AS have an increased risk of death from vascular causes, suggesting that these patients may require more aggressive risk factor management. Further studies are necessary to explore the role of primary prevention strategies in patients with AS.

Daratumumab, a novel treatment for relapsed Multiple Myeloma

Although proteasome inhibitors and immunomodulatory agents significantly improved multiple myeloma outcomes, most patients still relapse. CD38 is highly expressed on myeloma cells and less frequently expressed on normal lymphoid and myeloid cells. Daratumumab, a CD38 targeting monoclonal antibody, induces target-cell killing of CD38-expressing tumor cells. The NEJM published a phase 1 and 2 study of daratumumab for patients with relapsed myeloma[5]. 64% of the subjects had myeloma refractory to lenalidomide and bortezomib. In part 1 of the study, the dose-escalation phase, no maximum tolerated dose was found. In part 2, the dose-expansion phase, the 72 subjects were placed on different schedules of daratumumab at different doses (8 or 16mg/kg), infusion rates, and volumes until disease progression or a toxic event. No subject stopped treatment due to an infusion reaction. Subjects on schedule C (the lower dose, larger volume, and slower infusion rate) had less infusion reactions. All of the 30 subjects receiving 8mg/kg stopped due to progression of disease. Adverse events included fatigue, allergic rhinitis, pyrexia, pneumonia, thrombocytopenia, neutropenia, leukopenia, anemia, and hyperglycemia. Serious adverse events (most commonly infectious) occurred in 40% of the 8mg/kg cohort compared to 33% of the 16mg/kg cohort. The overall response rate (as measured by the reduction in M protein or free light chain and bone marrow plasma cells) was 10% in the 8mg/kg cohort vs 36% in the 16mg/kg cohort. The median duration of response was 6.9 months (95% CI 6.2-10.6) in the 8mg/kg cohort. The median duration of response was not reached by the 16 mg/kg cohort, with 65% (95% CI 28-86) of subjects still progression-free at 12months. This study shows that Daratumumab is a safe treatment option with a novel mechanism of action for refractory multiple myeloma. More specifically a dose of 16 mg/kg appears to be safer and more effective than 8mg/kg, but further studies including a phase 3 trial are needed to determine the efficacy of Daratumumab.

A promising dengue vaccine. 

This week, the NEJM published results from the efficacy surveillance phase and long-term safety phase of the CYD-TDV dengue vaccine trials[6]. CYD-TDV is a recombinant, live, attenuated, tetravalent vaccine against dengue fever. CYD-TDV underwent two phase 3 randomized intention-to-treat efficacy trials recruiting more than 31,000 children (2-16 years of age) in the Asian–Pacific region (CYD14 trial) and in Latin America (CYD15 trial). The safety of the vaccine was assessed in the long-term follow-up (from year 3 to 6) of the CYD14 and CYD15 subjects and in the CYD57 study, which is a 4-year follow-up of the phase 2b trial (CYD23) of participants in Thailand. Combined vaccine efficacies from the 2 trials showed no difference in efficacy in all patients. Upon multivariate analysis, stratification by age 9 years old showed an increased efficacy. Subjects above 9 years of age had an efficacy rate of 65.6% (95% CI 60.7-69.9) vs an efficacy rate of 44.6% (95%CI 28.4 to 80.3) in subjects below 9 years old. The number needed to treat for patients over 9 is 18 compared to 23 in those under 9. Safety was measured as the incidence of hospitalization for dengue to evaluate whether vaccinated subjects were at risk of increased severity of the disease. In the combined analysis of these 3 trials at years 3 and 4, vaccinated subjects of at least 9 years of age had a lower incidence of hospitalization for virologically confirmed dengue than the non-vaccinated group. This study suggests that the CYD-TDV is a safe and efficacious vaccine for dengue fever, which appears to have an age dependent increased in efficacy and safety. According to these study results, the vaccine may only be applicable to children greater than 9 years old. Further studies are necessary to confirm these findings and elucidate the etiology of the age dependent effects of the vaccine. 

Quick Cuts 

A preliminary 10-week phase 2 randomized multicenter, double-bind, placebo-controlled trial suggests that management of Alzheimer disease-related agitation with dextromethorphan hydrobromide-quinidine significantly improves the NPI Agitation/Aggression score of patients with moderate to severe symptoms requiring pharmacological interventions.[7]

A Public Health article in JAMA reviews strategies to target population-based health approaches to health risk factors with well-defined association to health outcomes.[8] This is an interesting read especially now that the current standards of radiation exposure and risks are being revisited by the Nuclear Regulatory Commission.[9] Of note, according to the International Atomic Energy Agency, there has been no disease or death related to the nuclear accident in Fukushima, but approximately 1,600 people died from evacuation-related causes. [10] 

The DATA-Switch study is a randomized controlled trial in postmenopausal osteoporotic women that showed that switching from teriparatide to denosumab continues to increase bone mineral density whereas the opposite switch leads to progressive or transient bone loss. [10]

A multicenter randomized control trial of the three sites for central venous catherization involving 3471 catheters placed in 3027 ICU patients showed a lower incidence of bacteremia and symptomatic thrombosis but higher incidence of pneumothorax in subclavian-vein catheterization compared to jugular-vein or femoral-vein catheterization.[11]

Although the investigation is still ongoing, soft cheeses distributed by Karoun Dairies might be the source of the Listeriosis outbreak that affected 24 people since 2010 in 9 states.[12]

Dr. Olivia Begasse De Dhaem is a medical intern at NYU Langone Medical Center

Peer reviewed by Ian Henderson, MD, Contributing Editor, Clinical Correlations

Image courtesy of University of Central Florida, Associated Press /Times Free Press.  


1. Pollack A. “Big Price Increase for Tuberculosis Drug Is Rescinded.” New York Times Business Day. September 21, 2015.®ion=top-news&WT.nav=top-news

2.  Opinion. “Should the Government Impose Drug Price Controls?” New York Times. September 23, 2015.

3.  Pritchard-Jones K, Bergeron C, de Camargo B, et al. “Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms’ tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.” The Lancet 2015; 386 (9999): pp 1156-1164.

4.  Haroon NN, Paterson JM, Li P, et al. “Patients With Ankylosing Spondylitis Have Increased Cardiovascular and Cerebrovascular Mortality: A Population-Based Study.” Ann Intern Med. 2015;163(6):409-416.

5.  Lokhorst HM, Plesner T, Laubach JP, et al. “Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.” N Engl J Med 2015; 373:1207-1219.

6.  Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, et al. “Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease.” N Engl J Med 2015; 373:1195-1206.

7.  Cummings JL, Lyketsos CG, Peskind ER, et al. “Effect of Dextromethorphan-Quinidine on Agitation in Patients with Alzheimer Disease Dementia A Randomized Clinical Trial.” JAMA 2015; 314 (12): 1233-1235.

8.  Chokshi DA, El-Sayed AM, Stine NW. “J-Shaped Curves and Public Health.” JAMA. Viewpoint September 21, 2015.

9.  Johnson G. “When Radiation Isn’t the Real Risk.” New York Times September 21, 2015.

10.  Leder BZ, Tsai JN, Uihlein AV, et al. “Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial.” The Lancet 2015; 386 (9999) pp 1147-1155.

11.  Parienti JJ, Mongardon N, Megarbane B, et al. “Intravascular Complications of Central Venous Catheterization by Insertion Site.” N Engl J Med 2015; 373:1220-1229.

12.  “Multistate Outbreak of Listeriosis Linked to Soft Cheeses Distributed by Karoun Dairies, Inc.” CDC Outbreaks. Sep 23, 2015.