An educational symposium for patients with sickle cell disease and their families: results from surveys of knowledge and factors influencing decisions about hematopoietic stem cell transplant.

BACKGROUND: The only available cure for sickle cell disease (SCD) is hematopoietic stem cell transplant (HSCT). One important barrier to HSCT in SCD is lack of patient and family knowledge. PROCEDURE: To improve awareness of HSCT as a curative option for SCD, we hosted half-day educational symposia in 2011 and 2012. Symposia included didactic lectures by HSCT experts, small group sessions, and question and answer sessions with SCD patients and their families who had undergone HSCT. In 2011, we distributed anonymous pre- and post-symposium knowledge tests to determine how much attendees had learned about transplant. In 2012, we asked attendees to rate the importance of various medical and psychosocial factors in the decision to pursue HSCT. RESULTS: Results from 2011 showed that knowledge about HSCT increased significantly after the symposium. Concern about the risk of transplant decreased slightly, but not significantly, following the symposium, and the majority of attendees expressed a desire to speak with physicians further about HSCT. In 2012, families reported that risk of death, prevention of SCD complications, and risk of serious complications were the most important considerations for their decisions about HSCT. CONCLUSIONS: A half-day symposium for SCD patients and their families can increase knowledge about HSCT. Education about risks and benefits of HSCT is key, as families consider these medical factors to be most important to their decision to pursue transplant. Our symposia can be replicated across the country to increase knowledge about HSCT for SCD and impact the number of patients who pursue HSCT.

Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN).

The Sickle Cell Unrelated Donor Transplant Trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a phase II study of the toxicity and efficacy of unrelated donor hematopoietic cell transplantation in children with severe sickle cell disease (SCD) using a reduced-intensity conditioning regimen. Here we report the results for the cord blood cohort of this trial. Eight children with severe SCD underwent unrelated donor cord blood transplantation (CBT) following alemtuzumab, fludarabine, and melphalan. Cyclosporine or tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. Donor/recipient HLA match status was 6 of 6 (n = 1) or 5 of 6 (n = 7), based on low/intermediate-resolution molecular typing at HLA -A, -B, and high-resolution typing at -DRB1. Median recipient age was 13.7 years (range: 7.4-16.2 years), and median weight was 35.0 kg (range: 25.2-90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 10(7) /kg (range: 3.1-7.6), and the median postthaw infused CD34 cell dose was 1.5 × 10(5) /kg (range: 0.2-2.3). All patients achieved neutrophil recovery (absolute neutrophil count >500/mm(3)) by day 33 (median: 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained, and 5 patients had autologous hematopoietic recovery. Six of 8 patients had a platelet recovery to >50,000/mm(3) by day 100. Two patients developed grade II acute GVHD. Of these, 1 developed extensive chronic GVHD and died of respiratory failure 14 months posttransplantation. With a median follow-up of 1.8 years (range: 1-2.6), 7 patients are alive with a 1-year survival of 100%, and 3 of 8 are alive without graft failure or disease recurrence. Based upon the high incidence of graft rejection after unrelated donor CBT, enrollment onto the cord blood arm of the SCURT trial was suspended. However, because this reduced-intensity regimen has demonstrated a favorable safety profile, this trial remains open to enrollment for unrelated marrow donor transplants. Novel approaches aimed at improving engraftment will be needed before unrelated CBT can be widely adopted for transplanting patients with severe SCD.

Risk factors for molecular detection of adenovirus in pediatric hematopoietic stem cell transplantation recipients.

Adenovirus (AdV) infections are a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). To evaluate the use of molecular AdV testing in HSCT at our institution and identify risk factors for AdV viremia and disease, we performed a retrospective cohort study of all HSCT recipients who had undergone AdV polymerase chain reaction testing over a 2-year period. Two cohorts were identified: cohort 1, comprising patients testing positive for AdV (n = 7) and cohort 2, comprising patients testing negative (n = 36). Overall patient characteristics were not statistically significantly different between the 2 cohorts. A comparison of cohort 1 and cohort 2 identified the following medication exposures as risk factors influencing AdV status: preparatory regimens using fludarabine (relative risk [RR], 8.73; 95% confidence interval [CI], 1.18-64.27; P = .006), melphalan (RR, 3.47; 95% CI, 0.76-15.94: P = .08), and/or cyclophosphamide (RR, 0.18; 95% CI, 0.02-1.4; P = .05), and GVHD prophylaxis with methylprednisone (RR, 3.73; 95% CI, 1.01-13.9; P = .04). AdV-positive patients had higher grades of GVHD and higher rates of GVHD of the gastrointestinal tract (RR, 4; 95% CI, 1.18-13.5; P = .03) compared with AdV-negative patients. Four of the 7 AdV-positive patients had concomitant clinical manifestations of disease, including pneumonia, diarrhea, and/or disseminated disease. Clinical outcomes in symptomatic patients included resolution of disease in 2 patients and death in 2 patients. All 7 AdV-positive patients received antiviral therapy, including 1 patient with severe disseminated disease that resolved after administration of liposomal cidofovir. Our study at a large pediatric HSCT center provides important preliminary data for the development of a prospective trial destined to identify specific HCST patient subpopulations that might benefit most from molecular screening and early preemptive therapy.

Amelioration of oral mucositis pain by NASA near-infrared light-emitting diodes in bone marrow transplant patients.

PURPOSE: This study seeks to investigate the use of extra-orally applied near-infrared phototherapy for the reduction of oral pain secondary to chemotherapy- and radiation therapy-induced mucositis in adult and pediatric hematopoietic stem cell transplant (HSCT) patients. METHODS: Eighty HSCT patients were divided into regular (R) and low (L) risk groups, then to experimental (E) and placebo (P) groups, resulting in four groups (ER, EL, PR, PL). Experimental subjects received 670 (± 10) nm gallium-aluminum-arsinide light-emitting diode device for 80 s at ~50 mW/cm(2) energy density and power exposure of 4 J/cm(2). Placebo patients received the same procedures, but with a placebo phototherapy (identical device but <5 mW/cm(2) energy density). Patients received their respective light therapy once per day starting on the day of the HSCT (day 0) and continued through day +14. Blinded evaluators examined the patients three times per week and scored their oral tissues and patient-reported pain assessments at each evaluation utilizing the WHO, NCI-CTCAE, and OMAS scales. RESULTS: Analysis of the mean scores at each observation demonstrate that the extra-oral application of phototherapy resulted in a significant reduction in patient-reported pain between the ER and PR patients (p < 0.05) at day +14 when graded via the WHO criteria. The ER and EL patients were improved in almost all other categories and assessment scales, but the differences were not statistically significant. CONCLUSION: Phototherapy demonstrated a significant reduction in patient-reported pain as measured by the WHO criteria in this patient population included in this study. Improvement trends were noted in most other assessment measurements.

Safety and efficacy of CMX001 as salvage therapy for severe adenovirus infections in immunocompromised patients.

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/µL (range, 7-1500 cells/µL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

CD34⁺ collection efficiency as a function of blood volumes processed in pediatric autologous peripheral blood stem cell collection.

PURPOSE: To characterize the relationship between CD34(+) collection efficiency and blood volumes processed in pediatric patients undergoing autologous peripheral blood stem cell (PBSC) collection. METHODS: Retrospective 8-year (2001-2009) study of pediatric patients (n = 79) with neuroblastoma and central nervous system (CNS) tumors undergoing first day of autologous PBSC harvest using MNC program on the COBE Spectra (Caridian BCT, Lakewood, CO) was performed. Patients undergoing 0 to 2.9 BV (standard volume), 3 to 6 BV (large volume), and greater than 6 BV (ultra large volume) harvests were evaluated for CD34(+) collection efficiency, diagnosis (neuroblastoma vs. nonneuroblastoma), disease type (primary vs. relapse), mobilization regimen, granulocyte colony stimulating factor (GCSF) dose, and apheresis complications. RESULTS: CD34(+) collection efficiencies (CE) for neuroblastoma patients were 67%, 50%, and 53% for standard (n = 14), large (n = 9), and ultra large (n = 5) volume harvests, respectively. Similarly, patients with nonneuroblastoma diagnoses had CD34(+) CE of 63%, 55%, and 65% for low (n = 19), large (n = 27), and ultra large (n = 5) volume harvests, respectively. Weight, granulocyte colony stimulating factor (G-CSF) stimulation, type of mobilization, and apheresis complications (normalized by run time) were similar between the standard, large, and ultra large volume groups in patients with either neuroblastoma or nonneuroblastoma diagnoses. CONCLUSIONS: CD34(+) collection efficiency in pediatric autologous PBSC collection on the first day of harvest does not decrease with higher numbers of blood volumes processed in patients with either neuroblastoma or nonneuroblastoma primary disease. These results indirectly indicate bone marrow CD34(+) cell mobilization occurs with longer apheresis procedures in pediatric patients.

Eradication of disseminated adenovirus infection in a pediatric hematopoietic stem cell transplantation recipient using the novel antiviral agent CMX001.

Adenovirus infection is a serious and often fatal complication in hematopoietic stem cell transplant patients. There are currently no FDA-approved therapies for adenovirus infection, with only anecdotal, off-label uses described for a variety of anti-viral agents or immune therapies. We report the first case of successful eradication of disseminated adenovirus infection by the novel antiviral agent CMX001 in a severely immunocompromised pediatric stem cell transplant recipient following failure to respond to intravenous cidofovir. Complete clinical and virologic response was documented; virologic and pharmacokinetic data are reported. CMX001 is a promising new oral antiviral agent under development for the prophylaxis and treatment of severe infections caused by double-stranded DNA viruses including adenovirus in immunocompromised patients.

The burden of cure: long-term side effects following hematopoietic stem cell transplantation (HSCT) in children.

Children who survive hematopoietic stem cell transplantation (HSCT) are at risk for an inordinate number of long-term side effects. Late effects can be secondary to the underlying diagnosis for which the transplant is performed, prior treatment of the disease, the transplant preparative regimen, treatment of the complications of transplant, and immunologic interactions between the graft and the host. This article describes the risks and manifestations of the most commonly reported late effects in survivors of pediatric HSCT.

Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia.

This open-label, dose-escalation study evaluated the safety and efficacy of single-agent gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted chemotherapeutic agent, for pediatric patients with multiple relapsed or primary refractory acute myeloid leukemia (AML). Twenty-nine children 1 to 16 years of age (relapsed disease, 19; refractory disease, 10) received gemtuzumab ozogamicin ranging from 6 to 9 mg/m2 per dose for 2 doses (separated by 2 weeks) infused over 2 hours. All patients had anticipated myelosuppression. Other toxicities included grade 3/4 hyperbilirubinemia (7%) and elevated hepatic transaminase levels (21%); the incidence of grade 3/4 mucositis (3%) or sepsis (24%) was relatively low. One patient treated at 9 mg/m2 developed veno-occlusive disease (VOD) of the liver and defined the dose-limiting toxicity. Thirteen patients underwent hematopoietic stem-cell transplantation less than 3.5 months after the last dose of gemtuzumab ozogamicin; 6 (40%) developed VOD. Eight of 29 (28%) patients achieved overall remission. Remissions were comparable in patients with refractory (30%) and relapsed (26%) disease. Mean multidrug resistance-protein-mediated drug efflux was significantly lower in the leukemic blasts of patients achieving remission (P < .005). Gemtuzumab ozogamicin was relatively well tolerated at 6 mg/m2 for 2 doses and was equally effective in patients with refractory and relapsed disease. Further studies in combination with standard induction therapy for childhood AML are warranted.