The non-steroidal anti-inflammatory drug salsalate provides safe and effective control of mucositis-unrelated pain during autologous and allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Pain is a serious adverse event which frequently accompanies hematopoietic stem cell transplantation (HSCT). The safety and efficacy of NSAIDS during HSCT is currently unknown. Salsalate is a platelet-sparing NSAID with a favorable toxicity profile compared with other NSAIDS. We report the safety and efficacy of salsalate for different types of pain during SCT. METHODS: We conducted a retrospective study of SCT recipients empirically treated with salsalate for > 48 h. Pain scores were assessed using the verbal rating scale for pain. A subset analysis of patients who received > 7 days of salsalate during periods of pancytopenia, mucositis, and other end-organ toxicities is included. RESULTS: Sixty-four patients, 42 auto- and 22 allografts, were identified. Reason for use: vertebral-related pain (30%), musculoskeletal (30%), and cytokine inflammatory pain syndromes (24%). Median dose 1500 mg/day, number of treatment days = 5, started on day+5 post-HSCT. Pain resolved/improved to pain score < 4 in 76% and stable in 15%. Forty-four patients (28-auto and 16 allografts) received > 7-day salsalate. Median WBC and platelet nadir were < 0.1 and 10,000 cells/ml respectively. EFFICACY: pain was improved or eradicated in 64% and stable in 32%. TOXICITY: LFT elevation (n = 2), elevated serum creatinine (n = 2), and minor bleed (n = 5-nose, gums, and urine). Salsalate discontinuation (n = 6): ineffective (n = 1), the liver (n = 1), the kidney (n = 1), > 5 platelet transfusions (n = 1), and vomiting (n = 2). There was no treatment related mortality. Salsalate was well tolerated, safe, and beneficial for several different types of pain during HSCT.

Risk factors and impact of non-Aspergillus mold infections following allogeneic HCT: a CIBMTR infection and immune reconstitution analysis.

Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic hematopoietic cell transplantation (HCT) diagnosed with either mucormycosis (n=72) or fusariosis (n=52) between days 0 and 365 after HCT are described and compared with a control cohort (n=11 856). Patients with NAMI had more advanced disease (mucormycois: 25%, fusariosis: 23% and controls: 18%; P=0.004) and were more likely to have a Karnofsky performance status (KPS) <90% at HCT (mucormycosis: 42%, fusariosis: 38% and controls: 28%; P=0.048). The 1-year survival after HCT was 22% (15-29%) for cases and was significantly inferior compared with controls (65% (64-65%); P<0.001). Survival from infection was similarly dismal regardless of mucormycosis: 15% (8-25%) and fusariosis: 21% (11-33%). In multivariable analysis, NAMI was associated with a sixfold higher risk of death (P<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GvHD, prior Aspergillus infection and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection and transplant before May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality and appears with similar frequency in the current antifungal era.

Polymicrobial bacterial or fungal infections: incidence, spectrum of infection, risk factors, and clinical outcomes from a large hematopoietic stem cell transplant center.

BACKGROUND: Infections cause significant morbidity and mortality for patients who undergo hematopoietic stem cell transplantation (HSCT). Cancer patients who develop polymicrobial infection (PI) are at increased risk for poor clinical outcomes, yet very limited data have been published within the HSCT setting. METHODS: An observational study of 901 stem cell transplant recipients was conducted at Northwestern Memorial Hospital to identify the incidence, risk factors and outcomes for HSCT recipients who develop infection(s) with multiple bacterial or fungal organisms. RESULTS: Among 901 HSCT recipients reviewed (675 autografts and 226 allografts), 237 patients (27%) had microbiologically documented microorganisms isolated, including 179 patients (76%) with monomicrobial infection and 59 patients (24%) with multiple microorganisms, of which 34 (14%) were classified as PI, and 25 (10%) as multiple distinct episodes of infection. CONCLUSION: The results show co-infection with multiple organisms during HSCT is relatively rare; however, these patients are at an increased risk for the development of acute graft-versus-host disease, delayed engraftment, and overall mortality.

Amphotericin B deoxycholate nasal spray administered to hematopoietic stem cell recipients with prior fungal colonization of the upper airway passages is associated with low rates of invasive fungal infection.

BACKGROUND: Invasive fungal infections cause major problems during hematopoietic stem cell transplantation (HSCT). Fungal colonization of the upper airway passages occurs frequently, and may serve as a portal of entry for potentially life-threatening fungal infections, especially in immunocompromised patients. METHODS: A clinical practice was instituted at Northwestern Memorial Hospital in Chicago in 2005, to administer amphotericin B deoxycholate nasal spray (ABNS) 0.5% to all HSCT recipients with fungal colonization of their nasal passages, in addition to standard oral antifungal prophylaxis. RESULTS: Among 1945 HSCT patients treated during the study period, 109 patients were identified with positive fungal surveillance cultures. CONCLUSION: Breakthrough fungal infections occurred in only 2 patients (2%), thus in this select group of HSCT recipients, ABNS administration is associated with a very low rate of breakthrough infection.

Antimicrobial prophylaxis in hematopoietic stem cell transplantation recipients: 10 years after.

BACKGROUND: Antimicrobial prophylaxis is recommended for all patients undergoing hematopoietic stem cell transplantation. Evidence-based guidelines recently have been updated to incorporate the results from recent clinical studies. METHODS: An antimicrobial prophylaxis survey was conducted during the 2013 ASBMT Tandem Meetings to discern the degree of concordance between transplant centers and society guidelines. RESULTS: The results show significant differences in prescribing practices among transplant institutions and variance with evidence-based guidelines. CONCLUSION: The clinical significance of this discordance is unknown.

Reporting of serious adverse events during cancer clinical trials to the institutional review board: an evaluation by the research on adverse drug events and reports (RADAR) project.

Global introspection is considered an unreliable method for attribution of causality of serious adverse events (SAEs), yet remains widely used for cancer drug clinical trials. Here, we compare structured case abstraction (SCA) to the routine method for detecting, evaluating, and reporting ADEs during cancer drug clinical trials to an Institutional Review Board (IRB). We obtained all SAE reports (2001-2008) received by one IRB for six clinical trials involving bevacizumab or oxaliplatin for treatment of gastrointestinal cancers. We compared the routine IRB SAE method to SCA for adverse event detection and causality attribution. Of 205 adverse events, 182 events (75%) were not reported; of these, 6 (20%) of 30 SAEs requiring an IRB report were unreported. For the 10 item Naranjo score, the amount of information useful for causality attribution was higher with SCA than the routine method (6.0 vs. 2.4 items, P < .0001). One-fifth of SAEs requiring an IRB report were unreported to the IRB via the routine method. SCA provided more useful information as to whether an SAE was caused by a cancer drug exposure. Our results suggest that SCA may improve SAE detection and the accuracy of attribution of causality during cancer drug clinical trials.

Effectiveness of a single 3-mg rasburicase dose for the management of hyperuricemia in patients with hematological malignancies.

Rasburicase was administered at a fixed dose of 3 mg to treat 287 episodes of elevated serum uric acid levels (>7 mg/dL) in 247 adult patients with hematological malignancies. The median total dose of 36 µg/kg (range: 18-65) was a fraction of the recommended total pediatric dose of 0.75-1.0 mg/kg. The median change in uric acid levels at 24 h was -4.1 mg/dL (range: -12 to +1) and -45% (range: -95 to +9). Uric acid levels normalized at 24 h in 72% of patients. There was no relationship between the weight-based dose and uric acid decline. The only predictor of success was the baseline uric acid; the failure rate was 84% with baseline level >12 mg/dL and 18% if it was ≤ 12. Uric acid levels continued to decline beyond 24 h in most patients without additional treatment. Serum creatinine remained stable over 24 h, and declined over 48 h and 7 days. There was no relationship between the extent of reduction in uric acid levels and serum creatinine. We conclude that a single 3-mg dose of rasburicase, used with close monitoring, is sufficient to treat most adults with uric acid levels up to 12 mg/dL.

Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring.

Concomitant use of tacrolimus and voriconazole, both competitive inhibitors of the CYP450 3A4 isoenzyme, requires tacrolimus dose reduction. On the basis of clinical observations, we developed a preemptive dose-reduction strategy in allograft recipients who received voriconazole to maintain tacrolimus concentrations within a target range. A total of 27 patients started i.v. tacrolimus at an average daily dose of 0.022 mg/kg on day -1 (30% lesser than the usual starting dose). The dose was reduced by 30-40% if the 48-h steady-state concentration was 7-10 ng/ml, and by 40-50% if it was 10-15 ng/ml. No change was made if the concentration was <7 ng/ml. Subsequently, concentrations were generally monitored 2-3 times a week with dose adjustments as necessary. None of the 170 levels (3-12 per patient; median 5) obtained between days +1 and +16 were subtherapeutic (<5 ng/ml) and only 34 levels (20%) were >15 ng/ml. Each patient required dose reduction at least twice. The dose had to be increased in only two patients after the initial dose reduction. The median tacrolimus doses in mg/kg declined with time; being 0.022, 0.008 and 0.006 on days 0, 7 and 14, respectively. We conclude that a preemptive dose-reduction strategy is effective in maintaining tacrolimus concentrations within the desired therapeutic range, although serial monitoring remains prudent.

Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project.

Granulocyte-colony stimulating factor (G-CSF) is widely administered to donors who provide peripheral blood stem cells (PBSC) for individuals who undergo hematopoietic stem cell transplants. Questions have been raised about the safety of G-CSF in this setting. Herein, the Research on Adverse Drug Events and Reports (RADAR) project investigators reviewed the literature on G-CSF-associated adverse events in healthy individuals or persons with chronic neutropenia or cancer. Toxicities identified included bone pain and rare instances of splenic rupture, allergic reactions, flares of underlying autoimmune disorders, lung injury and vascular events. Among healthy individuals, four patients developed splenic rupture shortly after G-CSF administration and three patients developed acute myeloid leukemia 1 to 5 years after G-CSF administration. Registry studies identified no increased risks of malignancy among healthy individuals who received G-CSF before PBSC harvesting. However, more than 2000 donors would have to be followed for 10 years to detect a 10-fold increase in leukemia risk. Our review identifies bone pain as the most common toxicity of G-CSF administration. There are questions about a causal relationship between G-CSF administration and acute leukemia, but more long-term safety data from database registries are needed to adequately evaluate such a relationship.

Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.

Seventy-one allograft recipients receiving voriconazole, in whom complete clinical, microbiologic and pharmacokinetic data were available, were studied to determine the efficacy of voriconazole in preventing fungal infections. The length of voriconazole therapy was 6-956 days (median 133). The total number of patient-days on voriconazole was 13 805 ( approximately 38 years). A total of 10 fungal infections were seen in patients on voriconazole (18% actuarial probability at 1 year): Candida glabrata (n=5), Candida krusei (n=1), Cunninghamella (n=1), Rhizopus (n=2) and Mucor (n=1). Two of the four zygomycosis cases were preceded by short durations of voriconazole therapy, but prolonged itraconazole prophylaxis. The plasma steady-state trough voriconazole levels around the time the infection occurred were <0.2, <0.2, 0.33, 0.55, 0.63 and 1.78 microg/ml in the six candidiasis cases. Excluding the four zygomycosis cases, all the six candidiasis cases were seen among the 43 patients with voriconazole levels of < or =2 microg/ml and none among the 24 with levels of >2 microg/ml (P=0.061). We conclude that voriconazole is effective at preventing aspergillosis. However, breakthrough zygomycosis is seen in a small proportion of patients. The role of therapeutic voriconazole monitoring with dose adjustment to avoid breakthrough infections with fungi that are otherwise susceptible to the drug needs to be explored prospectively.

Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy.

Zygomycosis is increasingly reported as a cause of life-threatening fungal infections. A higher proportion of cases reported over the last decades have been in cancer patients, with or without hematopoietic stem cell transplantation (HSCT). The new anti-fungal agent voriconazole is a recently identified risk factor for developing zygomycosis. We reviewed the clinical characteristics and outcomes of a large cohort of cancer patients who developed zygomycosis after exposure to voriconazole. Health care professionals at 13 large cancer centers provided clinical information on cancer patients with zygomycosis and prior exposure to voriconazole. Criteria for inclusion were 5 days or more of voriconazole use and diagnostic confirmation with tissue or histology. Fifty-eight cases were identified among patients with hematologic malignancies, 62% including patients who underwent a HSCT procedure. Fifty-six patients received voriconazole for primary or secondary prophylaxis against fungal infection. In addition to prior exposure to voriconazole, patients also had several of the previously established risk factors for zygomycosis. Amphotericin B was the most commonly prescribed anti-fungal therapy. Overall mortality was 73%. We conclude that zygomycosis after exposure to voriconazole is a recently described entity that is frequently fatal, despite treatment with currently available anti-fungal agents and surgery.

Reduced-dose rasburicase (recombinant xanthine oxidase) in adult cancer patients with hyperuricemia.

Recombinant urate oxidase (rasburicase) lowers uric acid levels rapidly to very low levels at the labeled dose of 0.15-0.2 mg/kg daily for 5 days. Our past experience showed that a lower dose (3 mg) lowered uric acid levels sufficiently in most patients. A retrospective review was conducted to determine the effect of a fixed 3 mg dose of rasburicase in 43 adult patients with cancer undergoing hematopoietic stem cell transplantation or receiving chemotherapy who had elevated or rising uric acid levels (6.4-16.8 mg/dl; median 9.6). Six patients received a second dose of rasburicase (3 mg in four patients and 1.5 mg in two patients) 24 h later. Patients received allopurinol, adequate hydration, as well as other supportive therapy as required. Uric acid levels declined by 6-95% (median 43%) within the first 24 h after rasburicase administration, and levels at 48 h were 9-91% (median 65%) lower than the baseline levels. Serum creatinine changed by < or =10% in 21 patients, increased by >10% in four patients and decreased by >10% in 18 patients. No significant renal dysfunction developed in any of the patients. We conclude that rasburicase is effective in lowering uric acid levels at a fixed dose of 3 mg, which is much lower than the recommended dose.

Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients.

Voriconazole, a new antifungal agent, is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. The clinical significance of this is unknown, and the utility of monitoring voriconazole levels is unclear. Steady-state trough plasma voriconazole levels were obtained in 25 allogeneic HSCT recipients using an HPLC assay. Patients had drug levels checked once (n=13), twice (n=10), or > or =3 times (n=2) 5-18 days (median 10) after starting voriconazole or dose modification. The 41 voriconazole levels were 0.2-6.8 microg/ml (median 1.6); 6 (15%) were <0.5 (possibly below the in vitro MIC90 for Aspergillus spp.). Voriconazole concentrations correlated with aspartate aminotranferase (AST) (r=0.5; P=0.0009) and alkaline phosphatase (r=0.34; P=0.03), but not with creatinine, bilirubin and alanine aminotransferase (ALT). Since liver dysfunction is common after HSCT, it was not possible to determine if elevated AST and alkaline phosphatase levels were the cause or the consequence of higher voriconazole levels. We conclude that trough voriconazole levels vary considerably between patients, and suggest monitoring levels in patients receiving voriconazole for confirmed fungal infections, and in those with elevated AST or alkaline phosphatase levels.

Antimicrobial prophylaxis in hematopoietic stem cell transplant recipients: heterogeneity of current clinical practice.

Antimicrobial agents are commonly used after hematopoietic stem cell transplant (HSCT) to prevent bacterial, viral and fungal infections. A pharmacy practice survey was undertaken to evaluate prevailing practices. The 31 centers evaluated transplanted over 3400 patients in 2001. Over half used bacterial prophylaxis; all with fluoroquinolones. A significantly higher proportion (90-100%) used fungal and viral prophylaxis. Most centers used fluconazole for fungal prophylaxis, but the dose used varied from 400 mg (the recommended dose) to 100 mg. Itraconazole and amphotericin preparations were used by some centers for allograft recipients because of their activity against aspergillosis. Most centers used brief viral prophylaxis for autograft recipients aimed at preventing HSV reactivation. Viral prophylaxis for allograft recipients was usually much more prolonged, reflecting concern over cytomegalovirus infections. Overall, there was significant deviation from recommended guidelines in many of the practices. Our survey suggests that substantial variation exists among transplant centers in their approach to antimicrobial prophylaxis after HSCT. This probably stems from the lack of definitive studies and strong recommendations in several areas, availability of newer agents that have not been adequately studied in the HSCT setting, and a desire to improve outcome before definitive studies are available for newer agents, a process that could take several years.

How long after neutrophil recovery should myeloid growth factors be continued in autologous hematopoietic stem cell transplant recipients?

Growth factors are routinely used after autotransplantation to accelerate hematopoietic recovery, and are continued until the absolute neutrophil count (ANC) is >/=0.5 x 10(9)/l on 3 consecutive days. Since ANC often increases to very high levels with this strategy, we discontinued growth factor on the first day ANC reached 0.5 x 10(9)/l in 45 patients (Study Group), and compared their subsequent ANC to 108 historic controls who received growth factor longer. While ANC on the day after reaching 0.5 x 10(9)/l was comparable between groups, ANC on the third day was significantly higher in the Control Group (2.3 vs 4.9 x 10(9)/l; P=0.0003). When compared to the first day, ANC in the Study Group was higher by a median of 140% on the third day and by 450% in the Control Group (P=0.0002). A significantly higher proportion of patients experienced a decline in ANC after the first day in the Study Group. However, only one patient in the Study Group became neutropenic transiently and ANC recovered spontaneously the next day. The incidence of fever and hospitalization were comparable. We conclude that growth factors can be discontinued after autotransplantation the day the ANC reaches 0.5 x 10(9)/l, without compromising neutrophil recovery.