An evaluation of ponatinib as a therapy in adult patients with resistant/intolerant chronic-phase chronic myeloid leukemia.

INTRODUCTION: Chronic myeloid leukemia is now a highly treatable leukemia due to the availability of multiple tyrosine kinase inhibitors (TKIs) inhibiting the BCR-ABL1 oncogene. Some patients with CML can display resistance or intolerance to multiple TKIs, oftentimes due to the presence of mutations in BCR-ABL1, such as T315I, which limits effective treatment options. Ponatinib is a third-generation, rationally-designed TKI with clinically meaningful activity in this difficult-to-treat population. Ponatinib is associated with an increased risk of arterial occlusive events (AOEs) which has required a reexamination of its dosing in order to limit the risk of these events. AREAS COVERED: This review will provide an overview of the mechanism of action of ponatinib and the safety and efficacy data from clinical trials in chronic myeloid leukemia. EXPERT OPINION: Ponatinib is a potent pan-BCR-ABL1 TKI with substantial activity in patients with more resistant or advanced CML. Its efficacy needs to be balanced with the increased risk of vascular events, which seems to be at least partially diminished by the implementation of mitigation strategies aimed at modifying cardiovascular risk factors and adaptive dosing of the drug.

Absolute lymphocyte count on the first day of thymoglobulin predicts relapse-free survival in matched unrelated peripheral blood stem cell transplantation.

Anti-thymocyte globulin (ATG) targets in-vivo T lymphocytes. Variations in the recipient absolute lymphocyte count (ALC) might result in a variable exposure of ATG. We hypothesized that recipient ALC on the first day of ATG might predict transplant outcomes. We evaluated 217 patients undergoing 8/8 HLA-matched unrelated donor (MUD) peripheral blood stem cell transplant (PBSCT) between January 2005 and December 2017, and receiving rabbit ATG (Thymoglobulin, total dose 4.5 mg/kg) on days -3, -2 and -1. With a median follow up of 3.68 years for survival (OS), one-year OS, relapse rate, non-relapse mortality (NRM), and relapse-free survival (RFS) were 64.7%, 15.9%, 25.8%, and 58.4%, respectively. Multivariable analysis revealed that ALC > 100 k/mm3 was associated with superior RFS (HR 0.64, p = .03). Our study indicates that ALC on the first day of thymoglobulin affects relapse-free survival in MUD PBSCT when weight-based thymoglobulin is used.

R-BEAM versus Reduced-Intensity Conditioning Regimens in Patients Undergoing Allogeneic Stem Cell Transplantation for Relapsed Refractory Diffuse Large B Cell Lymphoma.

Allogeneic stem cell transplant (alloSCT) is considered in diffuse large B cell lymphoma (DLBCL) patients with chemorefractory disease or who have relapsed after autologous SCT. Here we present the first report of alloSCT using the R-BEAM (rituximab, carmustine, etoposide, cytarabine, melphalan) conditioning regimen in DLBCL patients. We retrospectively compared long-term alloSCT outcomes of DLBCL patients who received either R-BEAM (n = 47) or reduced-intensity conditioning (RIC) regimens (n = 23). Seventy patients (median age, 53 years) with DLBCL received alloSCT between January 2005 and December 2017. The median number of pretransplant therapies was 3, and 17 patients (24%) received prior autologous SCT. All received rituximab as a frontline or salvage therapy before alloSCT. The donor was unrelated in 42 patients (60%), and peripheral blood stem cells were commonly used (96%). The 6-month cumulative incidence of grades III to IV acute graft-versus-host disease (GVHD) was 36.2% and 8.7% for R-BEAM and RIC, respectively (P = .03). Median follow-up of surviving patients after R-BEAM and RIC was 3.1 and 5.5 years, respectively. Three-year overall survival (OS) after R-BEAM and RIC was 34.4% and 43.4%, respectively (P = .48). At 3 years, R-BEAM was associated with a similar relapse rate (25.5% versus 26.1%, P = .96), nonrelapse mortality (NRM; 39.7% versus 39.1%, P = .98), and relapse-free survival (RFS; 34.8% versus 34.7%, P = .75) compared with RIC. In multivariable analysis lower Karnofsky performance score was associated with lower OS (hazard ratio, .96; P = .05), whereas chemorefractory disease was associated with a higher relapse risk (hazard ratio, 8.8; P = .04). No difference in OS, relapse, NRM, or RFS was noticed between R-BEAM and RIC. R-BEAM regimen seems to be feasible and results in equivalent rates of long-term OS, relapse, NRM, and RFS compared with RIC. However, a significantly higher rate of severe acute GVHD was noticed.

Liver Graft-Versus-Host Disease is associated with poor survival among allogeneic hematopoietic stem cell transplant recipients.

Liver Graft-versus-host disease (GVHD) is common in patients with post-transplant liver dysfunction following allogeneic hematopoietic stem cell transplantation (AHSCT). Oftentimes, the diagnosis is made clinically, and liver biopsy is deferred. Our objective was to evaluate the risk factors and clinical outcomes of liver GVHD among patients who developed post-transplant liver dysfunction. Additionally, we evaluated the feasibility of liver biopsy in this population. We compared outcomes between liver GVHD and a "non-liver GVHD" group, which consisted of other etiologies of post-transplant liver dysfunction. Between January 2003 and December 2010, 249 patients developed post-transplant liver dysfunction following AHSCT: 124 patients developed liver GVHD and 125 were in the "non-liver GVHD" group. The incidence of acute and chronic liver GVHD at one year was 15.7% and 31.0%, respectively. The competing risk analysis revealed full intensity conditioning regimen (Hazard ratio [HR], 1.76; P = .008) and related donor (HR, 1.68; P = .004) as independent risk factors for liver GVHD. The time-varying covariate Cox regression analysis with competing risk event, demonstrated that liver GVHD was independently associated with higher non-relapse mortality, and adverse relapse-free and overall survival. A total of 112 liver biopsies were performed in 100 patients. No major complications were observed. Liver biopsy confirmed prebiopsy hypotheses in 49% of cases, and led to treatment modification in 49% of patients. Our study shows that liver GVHD is associated with adverse survival. Liver biopsy is safe and often helps directing care in this setting.

Comparison of complications in midlines versus central venous catheters: Are midlines safer than central venous lines?

BACKGROUND: With the rising use of midline catheters (MCs), validation of their safety is essential. Our study aimed to evaluate the incidence of bloodstream infections (BSIs) and other complications related to the use of MCs and central venous catheters (CVCs). METHODS: A retrospective cohort study was performed at a tertiary care hospital in Detroit, Michigan, from March-September 2016. Adult patients with either MC or CVC were included. Outcomes assessed were catheter-related BSI (CRBSI), mechanical complications, hospital length of stay, readmission within 90 days of discharge (RA), and mortality. Statistical analysis was performed using SAS software. RESULTS: A total of 411 patients with MC and 282 patients with CVC were analyzed. More CRBSIs were seen in patients with CVC (10/282) than MC (1/411) (3.5% vs 0.2%, respectively; P = .0008). More mechanical complications were seen in patients with MC (2.6%) than CVC (0.3%; P = .03). Patients with CVC had a higher crude mortality (17.3% vs 5.3%; P < .0001), RA (58% vs 35%; P ≤ .0001), line-related RA (2.8% vs 0.2%; P = .0041), and transfer to intensive care unit after line placement (9% vs 5%; P = .01). CVC was a significant exposure for a composite of mortality, CRBSI, mechanical issues, thrombosis, and readmission because of a line-related complication (odds ratio, 3.2; 95% confidence interval, 1.8-5.8). CONCLUSIONS: Our findings show use of MC is safer than CVC, but larger studies are needed to confirm our findings.

Fluoroquinolone prophylaxis in autologous hematopoietic stem cell transplant recipients.

PURPOSE: Although fluoroquinolone prophylaxis is frequently utilized in autologous hematopoietic stem cell transplant (AHSCT) patients, its impact on morbidity and mortality is uncertain. This study investigates the role of quinolone prophylaxis after AHSCT in recent years. METHODS: We conducted a retrospective review of 291 consecutive adult patients who underwent AHSCT for malignant disorders, between June 2013 and January 2015. Outcomes were compared between patients who received norfloxacin prophylaxis and those who did not. The endpoints were mortality during prophylaxis and at 100 days after transplant, frequency of ICU admissions, and incidence and type of bacteremia. RESULTS: Of 291 patients, 252 patients received norfloxacin prophylaxis and 39 patients did not. The mortality during prophylaxis and at 100 days as well as the median number of days of hospitalization following AHSCT did not differ between the two groups. No differences were noted in the frequency of ICU admission, incidence of septic shock, and duration of ICU stay. Patients who did not receive prophylaxis had a significantly higher rate of neutropenic fever (97%) than patients who received prophylaxis (77%) (p = 0.005). The patients with prophylaxis demonstrated a significantly higher rate of gram-positive bacteremia as compared to those without prophylaxis (p = 0.002). Frequency of Clostridium difficile infection was similar during and post-prophylaxis. More antibiotic use was noted among patients without prophylaxis [97%; median 9 (range, 5-24) days] compared to patients with prophylaxis [79%; median 7 (range, 3-36) days, p = 0.04]. CONCLUSION: Although fluoroquinolone prophylaxis reduced the incidence of neutropenic fever and antibiotic use in AHSCT, it did not alter mortality or morbidity.