Primary graft dysfunction (PGD) is a potentially devastating complication of heart transplantation. Understanding the risk factors for PGD in the modern era of heart transplantation is of vital importance. This study investigated the relationship between post-left ventricular assist device (LVAD) right heart failure (RHF) and transplant outcomes. Patients with durable, continuous-flow LVADs who were transplanted between 2010 and 2016 at Barnes-Jewish Hospital were included in the study. Data collection was performed through retrospective chart review. The primary outcome was the incidence of PGD stratified by pretransplant incidence of RHF while on LVAD support. Among the 141 patients included in the study, 41 developed RHF. In the RHF cohort, 18 patients developed PGD as compared to 14 patients in the group without RHF (44% vs. 14%; p < 0.001). Mortality was significantly higher in the RHF group at 30 days (20% vs. 1%; p < 0.001) and 1 year (22% vs. 6%; p = 0.013). In a multivariable logistic regression model adjusted for confounding variables, RHF was associated with a nearly fourfold increased risk of PGD (odds ratio, 3.91; p = 0.003). The results of this study show that patients supported with LVADs who develop early severe RHF or late RHF are at increased risk of PGD and death following cardiac transplantation.
Letermovir is approved by the Food and Drug Administration for cytomegalovirus (CMV) prophylaxis in CMV seropositive recipients of allogeneic stem cell transplantation (alloSCT) up to day 100. Letermovir use up to day 100 after alloSCT has demonstrated a significantly lower incidence of clinically significant CMV infection (csCMVi) at 24 weeks and an overall mortality benefit as far as 48 weeks after transplantation. We report data on csCMVi incidence beyond 24 weeks and overall survival (OS) beyond 48 weeks and outcomes for patients who had a prior alloSCT, are CMV seronegative with seropositive donor (D+/R-), or are high risk (defined as those receiving haploidentical transplants, mismatched transplants, T-cell-depleted grafts, umbilical cord blood transplants, prednisone ≥1 mg/kg or equivalent steroid use, or the use of 2 or more immunosuppressants). Additionally, risk factors for CMV-related mortality and possible extended duration of letermovir are reported. This is a single-center, retrospective cohort study of 333 alloSCTs with CMV seropositive donors or recipients performed at Siteman Cancer Center and Barnes-Jewish Hospital from January 2016 to June 2019. The primary endpoint of csCMVi at day 180 was 19.46% with letermovir and 39.13% without letermovir (P < .0001). The secondary endpoints are as follows: day 100 csCMVi was 8.1% with letermovir and 34.8% without (P < .0001), day 365 csCMVi was 24.8% with letermovir and 41.3% without (P = .001). Our multivariate analyses demonstrated that exposure to letermovir was associated with improved OS (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.25-0.77), nonrelapse mortality (HR 0.50; 95% CI 0.27-0.94) and CMV-related mortality (HR 0.40; 95% CI 0.16-0.95) during day 0 to day 99 but worse CMV-related mortality during day 180 to day 364 (HR 3.19; 95% CI 1.29-7.92). Patients with serum IgG levels <400 mg/dL at day 100, high-risk transplants (P = .004), post-transplantation cyclophosphamide (PTCy; P = .001), and mismatched-unrelated donors (MMUD; P = .02) experienced increased CMV reactivation. The CMV D+/R- cohort demonstrated no difference in CMV reactivation overall (P = .19), but the subset receiving PTCy showed decreased reactivation with letermovir (P = .03). Discontinuation of letermovir at day 100 leads to increased incidence of late CMV reactivation and CMV-related mortality. Letermovir use in CMV recipient seropositive alloSCT may need to be extended. Serum IgG levels <400 mg/dL at day 100 was associated with increased CMV reactivation. Patients with subclinical CMV viremia before transplantation, high-risk transplants, PTCy, or MMUD had decreased CMV reactivation with letermovir. Although there was no difference in CMV reactivation in the CMV D+/R- cohort, the subset treated with PTCy for acute graft-versus-host disease prophylaxis had decreased CMV reactivation with letermovir.
Acute promyelocytic leukemia (APL) often presents with significant coagulopathy which may result in both hemorrhagic and thrombotic complications. The emergence of the COVID-19 pandemic has complicated the initial treatment and diagnosis of APL owing to the viral infection's own associated coagulopathy. Here we report two cases of APL newly diagnosed in the setting of COVID-19 infection and considerations in their management. Included is a discussion of strategies for the dosing of arsenic trioxide in patients with significant obesity and renal insufficiency. The case series submitted does not represent a study on patients and thus no specific informed consents or permissions were required. All images included in our manuscript have been deidentified and all authors certify that personal details that could potentially be used to identify the patients in the cases described have been removed. The corresponding author has personally confirmed that both patients included in this study have given verbal permission to present their cases in the de-identified manner as described above.
What is daunorubicin and cytarabine liposome? Daunorubicin and cytarabine liposome is the first dual-drug liposomal encapsulation product approved by the FDA. How does this drug work? Daunorubicin inhibits DNA and RNA synthesis by forming complexes with DNA, inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals. Cytarabine decreases DNA synthesis by inhibiting DNA polymerase. The fixed 1:5 molar ratio of daunorubicin:cytarabine was shown to be the most synergistic ratio for killing leukemia cells in vitro and in murine models. What is it approved for? Daunorubicin and cytarabine liposome is approved for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Daunorubicin and cytarabine liposome was approved based on results from an open-label, multicenter, randomized, phase III trial. Patients with newly diagnosed t-AML or AML-MRC between the ages of 60 and 75 years old were eligible for inclusion. A total of 309 patients were randomized to daunorubicin and cytarabine liposome or cytarabine and daunorubicin (7+3 or 5+2) induction and consolidation. The complete remission rate was higher with daunorubicin and cytarabine liposome (38% vs. 26%, p=0.036). Median event-free survival (2.5 vs. 1.3 months, p=0.021) and overall survival (9.6 vs. 5.9 months, p=0.005) were significantly better in patients who received daunorubicin and cytarabine liposome (J Clin Oncol 2016;34:15_suppl.7000). How do you administer this drug? Induction with daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 liposome is given intravenously over 90 minutes on days 1, 3, and 5. If second induction is needed, the same dose is given on days 1 and 3. Daunorubicin 29 mg/m2 and cytarabine 65 m/m2 liposome is given on days 1 and 3 for up to 2 cycles of consolidation. Are there any premedications needed for daunorubicin and cytarabine liposome? Prophylactic antiemetics, such as ondansetron and dexamethasone, should be administered prior to daunorubicin and cytarabine liposome since this medication has a moderate emetic risk. What are side effects associated with daunorubicin and cytarabine liposome (≥ 10%)? Side effects more commonly observed with daunorubicin and cytarabine liposome included (≥ 5% over control arm): Hematologic: hemorrhage, prolonged thrombocytopenia, prolonged neutropenia Infections: fungal, upper respiratory, catheter/device/injection site Other: rash, pruritus, cough, headache, visual impairment What are some other side effects? Patients may develop cardiotoxicity, hypersensitivity reactions, and tissue necrosis. Before administering daunorubicin and cytarabine liposome, the patient's cumulative anthracycline exposure should be calculated and assessed for appropriateness. Since daunorubicin and cytarabine liposome contains copper gluconate, copper overload may also occur. Are there any important drug interactions? Monitor cardiac and hepatic function at baseline and when used with other cardiotoxic and hepatotoxic agents, respectively. How do I adjust the dose in the setting of renal or hepatic insufficiency? Dose adjustments are not required for renal or hepatic insufficiency. Daunorubicin and cytarabine liposome is metabolized in the liver and excreted renally, but has not been studied in patients with severe renal impairment/end-stage renal disease or bilirubin levels greater than 3 mg/dL. Practical tips: If patients develop a hypersensitivity reaction, premedicate patients with an antihistamine and/or corticosteroid prior to subsequent doses. Do not interchange daunorubicin and cytarabine liposome with other daunorubicin and/or cytarabine products. Daunorubicin and cytarabine liposome has unique preparation instructions that pharmacy staff should be trained on. The total preparation time takes close to an hour with key steps including equilibration to room temperature, reconstitution followed by swirling vial contents, and aseptically transferring the medication to an infusion bag. What should my patients know? Patients should be educated on the administration schedule of daunorubicin and cytarabine liposome, as well as side effects, and contact their health care provider if they develop a hypersensitivity reaction, uncontrolled nausea or vomiting, or fever or chills. Side effects that patients should be educated on include low blood counts, increased risk of infection, hypersensitivity reactions, and cardiotoxicity. What else should I know? Daunorubicin and cytarabine liposome should only be used in patients with t-AML or AML-MRC. Patients who received daunorubicin and cytarabine liposome had more prolonged thrombocytopenia and neutropenia leading to increased infections and hemorrhage. Daunorubicin and cytarabine liposome has unique preparation instructions and should not be interchanged with other daunorubicin and/or cytarabine products. What useful links are available? https://vyxeos.com/ https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569950.htm Any ongoing clinical trials related to daunorubicin and cytarabine liposome? Multiple clinical trials with daunorubicin and cytarabine liposome are ongoing including trials in adult patients with newly diagnosed, relapsed/refractory AML, and myelodysplastic syndromes as well as exploration of use in the pediatric population. More can be found at https://clinicaltrials.gov. MALLORY L. CRAIN, PHARMD, is PGY2 Oncology Resident, Department of Pharmacy at Barnes-Jewish Hospital, St. Louis, Mo. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; and Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.Mallory L. Crain, PharmD: Mallory L. Crain, PharmDRamaswamy Govindan, MD: Ramaswamy Govindan, MD
Liposomal daunorubicin/cytarabine (CPX-351) gained FDA approval for secondary AML after demonstrating improved outcomes over daunorubicin and cytarabine (7 + 3). A number of study limitations prompted a comparison of safety/efficacy of CPX-351 against regimens containing a purine analogue and high-dose cytarabine (HIDAC). This retrospective study compared complete response rates with/without count recovery (CR/CRi) between HIDAC-based regimens and CPX-351 in 169 patients with newly diagnosed sAML. The CR/CRi rate was 62.7% in the HIDAC-based therapy arm vs. 47.9% in the CPX-351 arm (p = 0.002 [one-sided for non-inferiority]). Median time to absolute neutrophil and platelet count recovery was shorter after HIDAC-based therapy (18 and 23 days, respectively) compared to CPX-351 (36 and 38 days; p < 0.001). Median overall survival was 9.8 months in the HIDAC-based group and 9.14 months in the CPX-351 group. 30-day mortality was greater with CPX-351 (8.5%) compared to HIDAC-based (1.3%; p = 0.039). These results reveal comparable efficacy and favorable safety with HIDAC-based regimens.
