Evaluation of a primary antifungal prophylaxis protocol for preventing invasive mold infections after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Invasive mold infections contribute to morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. The optimal strategy for primary antifungal prophylaxis in this patient population remains uncertain. METHODS: Medical records of patients who underwent allogeneic hematopoietic stem cell transplantation between 1 January 2013 and 31 December 2017 were retrospectively reviewed. Adult patients were included if they received micafungin followed by fluconazole, with the option to escalate to voriconazole, for antifungal prophylaxis. The primary outcome was the incidence rate of proven or probable invasive mold infection. Secondary outcomes were time to invasive mold infection diagnosis, invasive mold infection-related mortality, and risk factors associated with invasive mold infection. RESULTS: Two hundred patients were included in the study, a majority of whom underwent matched unrelated (46%) or matched related (33%) donor transplants. The incidence rate of proven or probable invasive mold infection was 18.4 cases per 100 patient-years, with a one-year cumulative incidence of 14%. Median time to proven or probable invasive mold infection was 94 days post-transplant (IQR 26-178), with invasive mold infection-related mortality occurring in 18 (64%) of 28 patients diagnosed with invasive mold infection. Comparison of invasive mold infection-free survival by potential risk factors failed to show any significant differences. CONCLUSIONS: In this real-life cohort of allogeneic hematopoietic stem cell transplantation recipients, the incidence of proven or probable invasive mold infection was higher than expected based on previous literature. In the absence of standard guidance on anti-mold prophylaxis in this patient population and given that unique risk factors for invasive mold infection may differ between institutions, it is essential that centers performing allogeneic hematopoietic stem cell transplantation routinely monitor their antifungal prophylaxis strategies for effectiveness.

Defibrotide: An Oligonucleotide for Sinusoidal Obstruction Syndrome.

OBJECTIVE: To review the efficacy and safety of defibrotide as well as its pharmacology, mechanism of action, pharmacokinetics (PK), drug-drug interactions, dosing, cost considerations, and place in therapy. DATA SOURCES: A PubMed search was performed through August 2017 using the terms defibrotide, oligonucleotide, hepatic veno-occlusive disease (VOD), sinusoidal obstruction syndrome (SOS), and hematopoietic cell transplantation (HCT). Other data sources were from references of identified studies, review articles, and conference abstracts plus manufacturer product labeling and website, the Food and Drug Administration website, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: English-language trials that examined defibrotide's pharmacodynamics, mechanism, PK, efficacy, safety, dosing, and cost-effectiveness were included. DATA SYNTHESIS: Trials have confirmed the safety and efficacy of defibrotide for treatment of VOD/SOS in adult and pediatric HCT patients, with complete response rates and day +100 overall survival rates ranging from 25.5% to 76% and 35% to 64%, respectively. The British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation Guidelines recommend defibrotide prophylaxis in pediatric and adult HCT patients with risk factors for VOD/SOS; however, its prophylactic use in the United States is controversial. Although there are efficacy data to support this strategy, cost-effectiveness data have not shown it to be cost-effective. Defibrotide has manageable toxicities, with low rates of grade 3 to 4 adverse effects. CONCLUSIONS: Defibrotide is the first medication approved in the United States for the treatment of adults and children with hepatic VOD/SOS, with renal or pulmonary dysfunction following HCT. Data evaluating defibrotide for VOD/SOS prevention are conflicting and have not shown cost-effectiveness.

Dynamical System Modeling of Immune Reconstitution after Allogeneic Stem Cell Transplantation Identifies Patients at Risk for Adverse Outcomes.

Systems that evolve over time and follow mathematical laws as they evolve are called dynamical systems. Lymphocyte recovery and clinical outcomes in 41 allograft recipients conditioned using antithymocyte globulin (ATG) and 4.5-Gy total body irradiation were studied to determine if immune reconstitution could be described as a dynamical system. Survival, relapse, and graft-versus-host disease (GVHD) were not significantly different in 2 cohorts of patients receiving different doses of ATG. However, donor-derived CD3(+) cell reconstitution was superior in the lower ATG dose cohort, and there were fewer instances of donor lymphocyte infusion (DLI). Lymphoid recovery was plotted in each individual over time and demonstrated 1 of 3 sigmoid growth patterns: Pattern A (n = 15) had rapid growth with high lymphocyte counts, pattern B (n = 14) had slower growth with intermediate recovery, and pattern C (n = 10) had poor lymphocyte reconstitution. There was a significant association between lymphocyte recovery patterns and both the rate of change of donor-derived CD3(+) at day 30 after stem cell transplantation (SCT) and clinical outcomes. GVHD was observed more frequently with pattern A, relapse and DLI more so with pattern C, with a consequent survival advantage in patients with patterns A and B. We conclude that evaluating immune reconstitution after SCT as a dynamical system may differentiate patients at risk of adverse outcomes and allow early intervention to modulate that risk.

Serotonin-norepinephrine reuptake inhibitors for the management of chemotherapy-induced peripheral neuropathy.

OBJECTIVE: To review the literature evaluating serotonin-norepinephrine reuptake inhibitors (SNRIs) for chemotherapy-induced peripheral neuropathy (CIPN). DATA SOURCES: A PubMed search (1966-January 2014) was performed using the key terms serotonin-norepinephrine reuptake inhibitor, desvenlafaxine, duloxetine, milnacipran, venlafaxine, chemotherapy, and peripheral neuropathy. Bibliographies of select articles were examined for additional references and abstracts. STUDY SELECTION AND DATA EXTRACTION: Case reports and clinical trials published in English and conducted in humans were identified. All reports and trials evaluating a SNRI for the treatment of CIPN were included; 4 case reports, 1 open-label study, and 2 randomized controlled trials were identified for review. DATA SYNTHESIS: At present, no medications are approved for the treatment for CIPN. Emerging evidence suggests that venlafaxine and duloxetine may be effective for treating CIPN. Results of select trials report that these medications not only decrease pain but also relieve symptoms of numbness and tingling and improve the functional status and quality of life of patients suffering from CIPN. CONCLUSIONS: Evidence to support venlafaxine and duloxetine for the treatment of CIPN from oxaliplatin- or paclitaxel-based regimens is promising. Unfortunately, direct comparisons between venlafaxine and duloxetine do not exist, so definitive conclusions about which agent is preferred cannot be made. However, the breadth of data with duloxetine is larger, suggesting that it may be prudent to consider duloxetine first when choosing a SNRI for CIPN treatment. More robust trials are needed to establish their optimal place in therapy with regard to patient population, timing of therapy, dosing, and treatment duration.

Brentuximab vedotin: a CD30-directed antibody-cytotoxic drug conjugate.

Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), which is a subtype of non-Hodgkin lymphoma, are relatively uncommon lymphoproliferative types of cancer. These malignancies are highly curable with initial treatment. Nonetheless, some patients are refractory to or relapse after first- and second-line therapies, and outcomes for these patients are less promising. Brentuximab vedotin is a CD30-directed antibody-cytotoxic drug conjugate that has demonstrated efficacy in response rates (objective response rates and complete response) when given to patients with refractory or relapsed HL and sALCL. Although not compared directly in clinical trials, the response rates with brentuximab vedotin are higher than those of several current treatments for refractory or relapsed HL and sALCL. Adverse effects associated with brentuximab vedotin are considered manageable. Nonetheless, several serious adverse effects (e.g., neutropenia, peripheral sensory neuropathy, tumor lysis syndrome, Stevens-Johnson syndrome, and progressive multifocal leukoencephalopathy, resulting in death) have been reported with its use. Despite a lack of survival and patient reported outcome data, the United States Food and Drug Administration (FDA) granted accelerated approval to brentuximab vedotin for the treatment of HL after failure of autologous stem cell transplantation or at least two combination chemotherapy regimens, and for sALCL after failure of at least one combination chemotherapy regimen. With this approval, brentuximab vedotin is the first FDA-approved agent for the treatment of HL in over three decades and the first agent specifically indicated to treat sALCL. Results of ongoing prospective trials should determine if brentuximab vedotin has a survival benefit when compared directly with standard treatment and if brentuximab vedotin is safe and efficacious when given earlier in the disease process, or when used with other chemotherapy for the treatment of HL and sALCL or other CD30-positive malignancies.