Jennifer Schneiderman

Sequential therapy with activated prothrombin complex concentrates and recombinant FVIIa in patients with severe haemophilia and inhibitors: update of our previous experience

Summary.  Haemophilia patients with inhibitors can develop bleeding episodes, which are refractory to monotherapy with either recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrates (APCC). Management of such bleeds is often difficult. We previously reported the safety of using a combination of rFVIIa and APCC given in sequential fashion. In this report, we update our experience with sequential therapy. A retrospective review of medical records was conducted including all reports of sequential therapy defined as receiving both rFVIIa and APCC within 6 h. Data extracted included demographic data, treatment prior to and following hospital admission, clinical data including type and location of bleed, response to therapy, physical examination and laboratory data. In addition, for some patients, thromboelastography was performed to document the effect of sequential therapy on clot formation characteristics. Four patients comprising 35 admissions, 209 hospital days and 115 days of sequential therapy were included in the updated dataset. No patient developed thrombosis or overt disseminated intravascular coagulation (DIC) although elevations in the D‐dimer above 5 μg mL−1 were noted in 42% of the courses that lasted >3 days. Efficacy is suggested by the fact that patients had resolution of their bleeds after a median of 3 days of sequential therapy after failing to respond to a median of 3 days of monotherapy. Thromboelastography demonstrated an additive effect. Sequential therapy is a safe, potentially efficacious approach in the management of refractory bleeding episodes in patients with haemophilia and inhibitors.

Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe haemophilia and inhibitors

Summary.  Patients with haemophilia and inhibitors have bleeding episodes that can be refractory to home therapy with either activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa). Sequential therapy with these products has not been widely used because of concern regarding the possibility of thrombosis. This report describes the results of a retrospective chart review of five hospitalized children with severe haemophilia and inhibitors who have been treated with sequential doses of APCC and rFVIIa for refractory bleeding. These patients all had failed home therapy with APCC and rFVIIa alone. A total of 20 admissions were documented covering 170 hospital days, including 91 days of combination therapy. While being closely monitored in the hospital, they received alternating doses of APCC and rFVIIa every 6 h. Anywhere from one to three doses of rFVIIa were given every 2 h between APCC doses. Doses of APCC ranged from 35 to 80 U kg−1 dose−1, and doses of rFVIIa ranged from 80 to 225 mcg kg−1 dose−1. There was no clinical or laboratory evidence of thrombosis, thrombocytopenia, or disseminated intravascular coagulation (DIC). We found the combination of these factors to be safe and effective for patients with refractory bleeds. However, we recommend this aggressive therapy only in the inpatient setting with careful monitoring of the physical examination and frequent laboratory screening to assess for thrombosis and DIC, and without the concurrent use of antifibrinolytic medications.

Clinical Significance of MYCN Amplification and Ploidy in Favorable-Stage Neuroblastoma: A Report From the Children's Oncology Group

PURPOSE MYCN amplification is rarely detected in patients with favorable-stage neuroblastoma (NB). To determine the clinical significance of MYCN amplification in children with favorable-stage NB, we performed a retrospective review of data from the Pediatric Oncology Group (POG) biology study 9047. PATIENTS AND METHODS MYCN status, tumor cell ploidy, treatment, and outcome of patients with stage A, B, or Ds NB, enrolled on POG 9047 between 1990 and 1999 were analyzed. Event-free survival (EFS) and overall (OS) survival rates were analyzed using the Kaplan-Meier method. RESULTS Of the 1,667 patients enrolled on POG 9047, 643 had favorable-stage disease. Of these, follow-up data were available on 568 (34%) with stage A, B, or Ds disease and normal MYCN copy number, and 32 (1.9%) patients with MYCN-amplified, stage A, B, or Ds tumors. Within the cohort lacking MYCN amplification, the 7-year EFS and OS rates (+/- SE) were 91% +/- 1% and 96% +/- 1%, respectively. Patients with MYCN amplification had significantly worse EFS and OS (50% +/- 9% and 59% +/- 9%, respectively, P < .0001). Within the cohort of children with MYCN amplification, the 7-year EFS and OS rates were 80% +/- 10% and 87% +/- 9%, respectively for patients with hyperdiploid tumors and 25% +/- 11% and 38% +/- 12% for patients with diploid/hypodiploid NBs (P = .0063 and P = .0074, respectively). CONCLUSION Tumor cell ploidy may be a clinically useful factor for prognostication and treatment stratification in children with MYCN-amplified, favorable-stage NB tumors.

The use of fluid boluses to safely perform extracorporeal photopheresis (ECP) in low-weight children: A novel procedure

Apheresis procedures in small children are technically challenging and require special planning with attention to extracorporeal volume. Discontinuous procedures such as extracorporeal photopheresis (ECP) require additional consideration. Alternative methods to perform ECP have been utilized in small children that require manipulation of mononuclear cells outside the standard closed‐loop system. We present a safe and feasible alternative to the procedure for children who weigh less than 40 Kg, while maintaining a closed loop, sterile system utilizing the UVAR XTS device. A retrospective chart review was performed analyzing the use of fluid boluses (normal saline in those between 20 and 40 Kg, 5% albumin in those under 20 Kg) before ECP. Eleven patients underwent 334 ECP procedures for acute and chronic graft‐versus‐host disease (n = 9), and for prevention of graft‐versus‐host disease (n = 2). Volumes of fluid boluses were calculated based on the expected extracorporeal volume during the first draw cycle. Treatments consisted of at least three draw cycles using the 125 mL bowl. The median weight was 28.5 Kg (range 19 to 39); nine of 11 required red cell transfusions to maintain adequate hematocrit. Complications attributed to ECP included tachycardia, dizziness, nausea, and hypotension; these occurred either in combination or isolation in 31% of the procedures and resolved following additional fluid boluses. Only three (0.8%) required early photoactivation due to these complications. The median time to completion of treatment was 2 h and 58 min (range 1:30 to 5:03). ECP is well tolerated in low‐weight pediatric patients if hematocrit and hydration are carefully maintained. J. Clin. Apheresis, 2010.

Secondary malignant neoplasms after high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma

Outcomes for high‐risk neuroblastoma remain poor. Modern treatment protocols utilizing intense induction followed by myeloablative consolidation chemotherapy with autologous stem cell rescue (ASCR) have improved survival rates, but the long‐term sequelae, including development of secondary malignant neoplasms (SMN), are just now surfacing.

Correction of enzyme levels with allogeneic hematopoeitic progenitor cell transplantation in Niemann-Pick type B.

Niemann‐Pick type B (NP) is an autosomal recessive lysosomal storage disorder with variable phenotypes for which few patients have undergone hematopoietic progenitor cell (HPC) transplantation. We present an 18‐month old with NP type B who underwent two allogeneic HPC transplants from her HLA‐identical sister. Sphingomyelinase in the peripheral leucocytes and skin fibroblasts was absent at diagnosis. Engraftment failed following initial transplant; therefore a second with the same donor was performed. Engraftment since has been durable; all subsequent sphingomyelinase levels have been normal. Our experience indicates that HPC transplantation for patients with NP type B is feasible and beneficial. Pediatr Blood Cancer 2007;49:987–989.

Age-dependent pharmacokinetic profile of single daily dose i.v. busulfan in children undergoing reduced-intensity conditioning stem cell transplant

We studied the pharmacokinetic (PK) profile of single daily dose i.v. BU in children who underwent reduced-intensity conditioning (RIC) transplantation. A cohort of 19 patients ⩽4 years of age (group 1) and 33 patients >4 years (group 2) was studied. Patients received a BU test dose for PK studies, followed by two treatment doses adjusted to target an area under the curve (AUC) of 4000 μM min per day. Patients in group 1 attained a lower AUC as compared to group 2 (3568 vs 4035 μM min). In group 1, 67% patients and in group 2, 84% patients achieved AUC within the targeted range. Stable donor chimerism was achieved in 56% patients in group 1 and 79% in group 2. Eight patients required a second transplantation because of graft failure. Because of the concern that a low AUC adversely affected outcomes, a second cohort of 23 patients followed a modified protocol with a targeted AUC of 5000 μM min. A higher AUC was attained (4825 μM min). Stable donor chimerism was achieved in 91% of patients. Our results show that RIC regimens using two single daily doses of i.v. BU are effective in children, but a targeted AUC of 5000 μM min is recommended.

National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: Scientific Opportunities in Extracorporeal Photopheresis

The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresiss capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECPs induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012.

Extracorporeal photopheresis practice patterns: An international survey by the ASFA ECP subcommittee

Although many apheresis centers offer extracorporeal photopheresis (ECP), little is known about current treatment practices.

Report of the ASFA apheresis registry study on Wilson's disease

Wilsons disease is a rare autosomal recessive genetic disorder that results in accumulation of copper in the liver, brain, cornea and kidney. Therapeutic plasma exchange (TPE) has been used to remove copper and provide a bridge to liver transplantation. We report here the collective experiences through the ASFA apheresis registry on Wilsons disease.