Pediatric Hematopoietic Stem Cell Transplantation Recipients Research Articles

Risk factors for hemorrhagic cystitis in pediatric allogeneic hematopoietic stem cell transplant recipients.

Hemorrhagic cystitis (HC) results in significant morbidity among hematopoietic stem cell transplant (HSCT) recipients. Several potential causes for HC have been postulated, including viral infection, but definitive evidence is lacking, particularly in pediatric HSCT patients. Ninety pediatric HSCT recipients were prospectively tested on a weekly basis for adenovirus (ADV) and BK virus (BKV) by quantitative real-time polymerase chain reaction in blood and urine samples. Results were correlated with the occurrence of grade II-IV HC. The odds ratio (OR) of HC (95% confidence interval) for BKV ≥1×10(9) copies/mL of urine was 7.39 (1.52, 35.99), with a P-value of 0.013. Those with acute graft-versus-host disease (aGVHD) also had higher odds of developing HC, with an OR of 5.34. Given a 20% prevalence rate of HC, positive and negative predictive values of 29% and 95% were seen with a cutoff of 10(9) copies/mL. BK viremia did not reach significance as a risk factor for development of HC (P=0.06). Only 8 patients showed ADV viruria and 7 showed ADV viremia; all had low viral loads and 4 had no evidence of HC. HC in pediatric HSCT is correlated most strongly to elevated urinary viral load of BKV and to aGVHD, but less strongly to BK viremia.

Use of the Japanese Live Attenuated High-Titer Varicella Vaccine in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Background: Hematopoietic stem cell transplantation (HSCT) recipients carry a high risk of primary varicella and varicella-zoster virus (VZV) reactivation. VZV infections can be fatal, and VZV reactivation can be complicated by postherpetic neuralgia, which worsens the recipients’ post-HSCT quality of life. VZV vaccines may prevent such infections; however, international vaccination guidelines do not recommend VZV vaccination of HSCT recipients because few data regarding safety among HSCT recipients are available. In Japan, we use a high-titer Oka stain vaccine for varicella vaccination and zoster prevention in the elderly; the plaque forming unit (PFU) value of this vaccine is as high as the zoster vaccine used in the U.S. Data regarding the safety of zoster vaccine in HSCT recipients is limited; therefore, we report our experience with this high-titer zoster-equivalent varicella vaccine in pediatric allogeneic HSCT recipients.Patients and Methods: Forty-seven pediatric allogeneic HSCT recipients who underwent transplantation at the Saitama Children’s Medical Center from 2000-2011 were vaccinated with live vaccines and their antibody titers were evaluated after vaccination. Among the 47 recipients, the Japanese high-titer varicella vaccine was administered to 32 recipients. Since establishing the live vaccine initiation criteria in 2009, allogeneic HSCT recipients were considered as recipients for live vaccines, including the varicella vaccine, if 24 months had passed after HSCT without active chronic GVHD or required immunosuppression. In addition, recipients were required to have a lymphocyte count >1500/μl or CD4 cell count >700/μl if they were <6 years and a lymphocyte count >1000/μl or CD4 cell count >500/μl if they were >6 years, normal phytohemagglutinin response, and serum IgG level >500 mg/dL. Before 2009, time for vaccination depended on each doctor’s judgment. Patients were given a single dose of the Biken varicella vaccine containing a minimum of 23,000 PFUs. We use EIA to measure the antibody titer and defined seropositivity as a titer >6.0. The time to evaluate the antibody titer was not fixed. We retrospectively collected the clinical data of recipients and laboratory data by reviewing the medical records.Results: The 32 recipients, who received the Japanese varicella vaccine, underwent HSCT at a median age of 5.15 years (range: 0.5-16.4 years) and were vaccinated at a median of 20.65 months (range: 4.8-112.1 months) after HSCT. Twenty and 11 patients had received myeloablative and nonmyeloablative conditioning, respectively. Nine patients received related-donor transplant, of which eight were bone marrow and one was peripheral blood. Twenty-three patients received unrelated-donor transplant, of which 14 were bone marrow and nine were cord blood. Antithymocyte globulin was administered to four patients. Eighteen of the 32 patients (56.3%) were seropositive after vaccination. Of the 26 patients, whose vaccination histories and pre-transplantation histories were available, eight were affected by natural disease, six had been immunized, and 12 had not been immunized. At vaccination, the median lymphocyte count was 3201/μl (range: 817-6630/μl) and the median IgG value was 880 mg/dL (range: 233-1461 mg/dL). There was no significant risk factor associated with vaccine failure. We experienced one case of varicella because of wild type VZV and no cases of zoster after vaccination during a median follow-up period of 4.8 years (range: 0.4-11.3 years); the single patient developed varicella 13 days after vaccination, immediately after an influenza virus infection. Whereas, two cases of varicella and one case of zoster developed before vaccination. Of the other 15 recipients, who did not receive varicella vaccine, three varicella and two zoster developed in three recipients.Conclusion: We safely vaccinated pediatric allogeneic HSCT recipients with the Japanese high-titer varicella vaccine. This finding could encourage the use in the U.S. of zoster vaccines such as Zostavax@, which contains similarly high PFUs, and low-titer varicella vaccines such as Varivax@. However, the efficacy of high-titer varicella vaccines for preventing VZV reactivation in this population remains unclear. Further studies are warranted to elucidate the efficacy and difference between low-titer and high-titer varicella and zoster vaccines. DisclosuresNo relevant conflicts of interest to declare.

Treosulfan-Based Conditioning in Pediatric Hematopoietic Stem Cell Transplantation: A Prospective Study on Pharmacokinetics and Early Clinical Outcomes

▪IntroductionTreosulfan is an alkylating agent which is increasing applied in regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT) in children. It has strong myeloablative and immunosuppressive activity and, in comparison with busulfan and total body irradiation, a relatively mild toxicity profile. The optimal dose of treosulfan in pediatric patients, remains to be established. To optimize the balance between treosulfan efficacy and toxicity, pharmacokinetic (PK) monitoring may be a valuable tool. With this purpose, we recently developed a PK and limited sampling model (LSM) which allows measurement of treosulfan exposure. We here report the first results of an ongoing prospective study on the relation between the pharmacokinetic profile of treosulfan in pediatric HSCT recipients and clinical outcome.Materials and MethodsChildren (n =26; ≤ 18 years) receiving treosulfan based conditioning prior to their first HSCT in the Leiden University Medical Center, The Netherlands were included. Patients ≥ 1 year of age received treosulfan in a dose of 42 g/m2, divided over 3 days. Two patients aged 1.5 and 7 months received 30 and 36 g/m2, respectively. Treosulfan was combined with fludarabine (30 mg/m2/day, 5 days) in all patients and in n=20 patients thiotepa (8 mg/kg) was added. Serotherapy consisted of anti-thymocyte globuline or alemtuzumab. Blood samples were collected at 1.5, 3.5, 4, 5, 7 and 9 or, when a LSM was applied, at 4-5 and 6-7 hours after the start of a three hour treosulfan infusion. The individual PK profile of each patient was determined by a population PK-model with a one-compartment model. Clearance and volume of distribution were allometrically scaled using body weight, with a fixed scaling exponent of 0.75 and 1.0, respectively.Clinical endpoints of this study were stem cell engraftment, chimerism, GvHD, organ toxicity, relapse and treatment related mortality.ResultsThe median age, clearance, and volume of distribution were 6.5 (0.13-16.8) years, 7.8 L/h (1.2 - 44.7 L/h), and 13.8 L (3.0 - 42.9 L), respectively. Within the n=24 patients receiving 42 g/m2, the mean AUC of treosulfan was 1502 mg*h/L and the inter-patient variability was 14%. The inter-occasion variability was 5.4%, based on the day 1 and day 3 results of 12 patients. Two patients received a lower dose of 30 g/m2 and 36 g/m2, resulting in a day 1 AUC of 1578 mg*h/L and 1349 mg*h/L, respectively. A linear relationship was observed between age and treosulfan exposure (R2 = 24%) and body surface area and treosulfan exposure (R2 = 29%), resulting in a lower exposure in older patients (Figure 1.)In this cohort overall survival is 21/26 (81%). Four patients died prior to engraftment (≤18 days after HSCT), due to infection, toxicity (n = 2) and active malignant disease. Treosulfan exposure in these four patients was similar to the remaining patients of the cohort. Primary engraftment was seen in 95% of the 22 evaluable patients. Of the 21 survivors, 76% are disease free, four patients had a recurrence of initial disease, and one patient had a primary rejection followed by rapid autologous reconstitution. In 46% of the patients mucositis grade 2 or 3 was observed, 23% of the patients had skin toxicity grade 1-2 and 31% had a moderate and transient hepatic toxicity within 28 days after treosulfan administration. Acute GvHD ≥ grade II occurred in 3/26 patients. Severe hepatic toxicity occurred in three patients that received treosulfan as reduced toxicity conditioning because of their pre-existing organ toxicity. No association between treosulfan exposure and primary engraftment, survival and disease status at last follow-up was observed. Furthermore, the higher treosulfan exposure in the younger patients was not correlated with higher toxicity levels.ConclusionOur results demonstrate that PK monitoring provides novel insight in the level and inter-patient variability of treosulfan exposure in pediatric patients. To further improve early and long term clinical outcome in pediatric HSCT recipients individualized, age and possibly disease-specific dosing regimens may in the end be required. To achieve this goal, treosulfan PK monitoring as reported here will be a pivotal instrument to obtain further insight into the correlation between treosulfan dose and clinical outcome parameters. With this aim, we are currently performing a prospective multicenter pediatric study in disease-specific cohorts. [Display omitted] DisclosuresOff Label Use: Treosulfan in conditioning prior to allo-HSCT in pediatric patients.

The Effect of Cidofovir on Adenovirus Plasma DNA Levels in Stem Cell Transplantation Recipients without T Cell Reconstitution

Cidofovir is frequently used to treat life-threatening human adenovirus (HAdV) infections in immunocompromised children after hematopoietic stem cell transplantation (HSCT). However, the antiviral effect irrespective of T cell reconstitution remains unresolved. Plasma HAdV DNA levels were monitored by real-time quantitative PCR during 42 cidofovir treatment episodes for HAdV viremia in 36 pediatric allogeneic HSCT recipients. HAdV load dynamics were related to T and natural killer (NK) cell reconstitution measured by flow cytometry. To evaluate the in vivo antiadenoviral effect of cidofovir, we focused on 20 cidofovir treatment episodes lacking concurrent T cell reconstitution. During 2 to 10 weeks of follow-up in the absence of T cells, HAdV load reduction (n = 7) or stabilization (n = 8) was observed in 15 of 20 treatments. Although HAdV load reduction was always accompanied by NK cell expansion, HAdV load stabilization was measured in 2 children lacking both T and NK cell reconstitution. In cases with T cell reconstitution, rapid HAdV load reduction (n = 14) or stabilization (n = 6) was observed in 20 of 22 treatments. In the absence of T cells, cidofovir treatment was associated with HAdV viremia control in the majority of cases. Although the contribution of NK cells cannot be excluded, cidofovir has the potential to mediate HAdV load stabilization in the time pending T cell reconstitution.

Future of Allogeneic Hematopoietic Stem Cell Transplantation for Chemotherapy-Resistant Pediatric Acute Leukemia: Potential Advances

Fred Hutchinson Cancer Research Center, Seattle, WA, USA University of Washington Department of Pediatrics, Seattle, WA, USA Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, USA *Author for correspondence: Tel.: +1 206 667 6572; Fax: +1 206 667 7983; mbleakle@fhcrc.org Transplantation as a curative strategy for high-risk leukemia Allogeneic hematopoietic stem cell transplantation (HCT) is curative for many children with life-threatening, chemotherapy-resistant leukemia. HCT works by two major mechanisms: high-intensity chemotherapy, or chemoradiotherapy pretransplant conditioning; and an immunologic antileukemia effect mediated by donor lymphocytes in the graft, the ‘graftversus-leukemia effect’ (GVL). Survival rates for pediatric leukemia HCT recipients have steadily increased over time with current overall survival rates for pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) of >50%. The improvements in survival principally reflect major reductions in early postHCT treatment-related mortality (TRM) that have occurred as a result of better supportive care. The decrease in TRM in unrelated donor, cord blood (CBT) and mismatched family donor HCT has been particularly notable, and survival rates after ‘alternative donor HCT’ are now broadly comparable to HLA-matched sibling donor HCT. Unfortunately, relatively little reduction has been achieved in relapse rates, making relapse now the most frequent cause of failure of HCT for leukemia [1]. Relapse occurs in 10–30% of HCTs performed for pediatric leukemia in remission and has a dismal prognosis: the median survival of children with postHCT relapse is 4 months [2]. In order to further improve overall survival after allogeneic HCT for pediatric leukemia, novel strategies to address post-HCT leukemia relapse are crucial.

A Comparison of Bronchoalveolar Lavage versus Lung Biopsy in Pediatric Recipients after Stem Cell Transplantation

Bronchoalveolar lavage (BAL) has been a useful initial diagnostic tool in the evaluation of pulmonary complications after hematopoietic stem cell transplantation (HSCT); however, the diagnostic sensitivity, prevalence, and outcome after BAL versus lung biopsy (LB) in pediatric HSCT patients remains to be determined. We reviewed 193 pediatric HSCT recipients who underwent a total of 235 HSCTs. Sixty-five patients (34%) underwent a total of 101 BALs for fever, respiratory distress, and/or pulmonary infiltrates on chest radiograph and/or computed tomography scan. The 1-year probability of undergoing BAL was 43.0% after allogeneic stem cell transplantation (alloSCT) and 8.5% after autologous stem cell transplantation (autoSCT) (P = .001). Sixteen of the 193 patients (8%) patients underwent 19 LBs. The probability of undergoing LB at 1 year after HSCT was 9.3%. No grade III or IV adverse events related to either procedure were observed. Of the 101 BALs performed, 40% (n = 40) were diagnostic, with a majority revealing a bacterial pathogen. Among the 19 LBs performed, 94% identified an etiology. In multivariate analysis, myeloablative conditioning alloSCT conferred the highest risk of requiring a BAL (hazard ratio [HR],8.5; P = .0002). The probability of 2-year overall survival was 20.2% in patients who underwent BAL, 17.5% for patients who underwent biopsy, and 67.4% for patients who had neither procedure. In multivariate analysis, only the requirement of a BAL was independently associated with an increased risk of mortality (HR, 2.96; P < .0001). In summary, in this cohort of pediatric HSCT recipients, BAL and LB were used in approximately 35% and 8% of pediatric HSCTs with diagnostic yields of approximately 40% and 94%, respectively, and were both associated with poor long-term outcomes.

Frequent Occurrence of Cytomegalovirus Retinitis During Immune Reconstitution Warrants Regular Ophthalmic Screening in High-Risk Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients

Although cytomegalovirus (CMV) retinitis (CMVR) is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT), standard operating procedures for ophthalmic monitoring are variable. In particular, authors perceived a greater risk of CMVR after pediatric HSCT for inherited immunodeficiencies, in patients who often have pretransplantation viremia. This study was therefore performed to identify high-risk pediatric HSCT recipients who would benefit from regular ophthalmic monitoring. During a 5-year study period, we retrospectively analyzed findings in 56 of 304 consecutive HSCT recipients (age range, 0.5-197 months) in whom significant CMV viremia developed (CMV level at PCR, ≥4000 copies/mL). All HSCT recipients with significant CMV viremia underwent retinal examination weekly (inpatients) or every other week (outpatients), with examinations performed by a skilled ophthalmologist. CMVR developed in 13 (4%) of 304 HSCT recipients, 23% (13 of 56) of those with significant CMV viremia. Pretransplant viremia (odds ratio, 11.3; P < .01), acute (grade ≥2) graft-vs-host disease (odds ratio, 8.2; P < .02) and mismatched graft (odds ratio, 8; P < .02) were identified as independent risk factors. Compared with other invasive CMV diseases, CMVR was more often a late-onset disease, occurring at a median of 199 days after HSCT. At diagnosis, a significantly higher CD4 T-cell count (≥200/µL; P < .03) and a lower CMV load (P < .004) was observed in children with CMVR, compared with those in whom lung, gut, or liver CMV disease developed. We report an increased risk of CMVR in high-risk pediatric HSCT recipients. This form of CMV disease differs from other invasive CMV disease in its relationship to immune reconstitution and viral dynamics. We have studied the relationship between these variables and suggested a risk-stratified ophthalmic screening strategy.

Epidemiology of Chronic Graft-Versus-Host Disease in the Pediatric Recipients of Hematopoietic Stem Cell Transplantation

Most studies into the epidemiology of chronic graft-versus-host- disease (cGVHD) have focused on adult hematopoietic stem cell transplant (HSCT) recipients. To determine whether the clinical factors that contribute to the development of cGVHD in pediatric HSCT recipients differed from those implicated in adult HSCT recipients, we undertook a cross-sectional, single institution study of pediatric HSCT recipients who were more than one year following their myeloablative HSCT. Pediatric recipients were transplanted between 1998 and 2011. Thirty-one (31) recipients with either active (14) or resolved (17) cGVHD were identified and compared to 47 pediatric HSCT recipients without cGVHD [40 recipients with no history of acute GVHD (Grade II-IV) and 7 recipients with a history of only acute GVHD]. All clinical records were re-evaluated by a single observer and graded for the severity of both acute and cGVHD using the NIH Consensus Scoring Criteria. Recipients’ clinical characteristics were determined. Among the variables that did not differ significantly between HSCT recipients with and without cGVHD were: recipient age, donor age (of bone marrow donors), use of TBI containing preparative regimes, malignant versus non-malignant diseases, and female donor/male recipient. The use of bone marrow as the HSC source, matched related donors, and the absence of acute GVHD were all associated with a decreased probability of cGVHD. No significant differences were identified between the patients who had active cGVHD and those who had resolved cGVHD.

Psychosocial Changes Associated With Participation in Art Therapy Interventions for Siblings of Pediatric Hematopoietic Stem Cell Transplant Patients

Hematopoietic stem cell transplantation (HSCT) is an accepted medical treatment for many serious childhood diseases. HSCT is a demanding procedure that creates both physical and emotional challenges for patients and their family members. Research has demonstrated that siblings of children undergoing HSCT are at risk for developing psychosocial problems such as posttraumatic stress, anxiety, and low self-esteem. This study examined psychosocial changes in siblings (N = 30) of pediatric HSCT recipients. These siblings participated in an art therapy intervention session 1 week, 1 month, and 3 months after their siblings’ HSCT procedure. Results showed improvements in sibling psychosocial functioning associated with participation in the art therapy interventions. Compared to a control group (n = 10), the intervention group (n = 20) showed lower levels of posttraumatic stress symptoms at the final session.

Patient, Virus, and Treatment-Related Risk Factors in Pediatric Adenovirus Infection after Stem Cell Transplantation: Results of a Routine Monitoring Program

Human adenovirus (HAdV) infection after hematopoietic stem cell transplantation (HSCT) is associated with significant morbidity and mortality in children. The optimal surveillance and treatment strategies are under discussion. Here, we present data from 238 consecutive pediatric allogeneic HSCT recipients who underwent transplantation in a single center who were included in a prospective, weekly HAdV DNAemia monitoring program by quantitative PCR. HAdV loads >1000 copies/mL were detected in 15.5% of all patients. Despite a low mortality directly attributed to HAdV infection (2 patients, 0.84%), blood HAdV loads >10,000 copies/mL (6.7% of all patients) were significant and independent risk factors for poor survival. We searched for patient, virus, and treatment-related risk factors of HAdV DNAemia and disease. Detection of HAdV in blood before day 50 post transplantation was a major independent risk factor for the development of blood HAdV loads >10,000 copies/mL. HAdV typing revealed A31, C1, and C2 as the predominant pathogens among several other HAdV strains with type C species detected in most patients with severe HAdV disease. Stool HAdV loads were prospectively monitored in 111 patients and correlated with but did not significantly precede detection in blood. Treatment with cidofovir led to stable or reduced viral load in 70% of patients with blood HAdV loads >1000 copies/mL. Thus, early occurrence of HAdV-DNA in blood of pediatric HSCT recipients predisposes for development of high viral loads. Control of HAdV infections was attempted by preemptive cidofovir treatment of patients with high blood HAdV loads or with symptomatic organ infections and correlated with low HAdV-attributed mortality.

Imprint Of Early CMV Reactivation On The Reconstituting T-Lymphocyte Compartment One and Two Year After Hematopoietic Stem Cell Transplantation

BackgroundCytomegalovirus (CMV) reactivation frequently occurs during early immune reconstitution after hematopoietic stem cell transplantation (HSCT). Although CMV is associated with accelerated immune ageing in healthy individuals, the impact of early CMV reactivation on T-cell immunity long term post HSCT is unknown. In this study, we report the impact of early CMV reactivations on the reconstitution and composition of the T-lymphocyte compartment one to two year after HSCT in a large cohort of pediatric HSCT recipients. MethodsWe analyzed the lymphocyte compartment one and two year after transplantation in 131 consecutive (2002 - 2011) pediatric HSCT recipients that were eligible for follow up one year post HSCT. Viral infections were routinely monitored by weekly serum viral DNA PCR in the first 100 days. Peripheral blood mononuclear cells were routinely analyzed by multicolor flow cytometry. Six patients with early CMV reactivation and an HLA type for which CMV-tetramers were available were analyzed for the presence and phenotype of CMV-specific CD8+ T-lymphocytes. ResultsOne year post HSCT, patients with early CMV reactivation (n = 46, PCR ≥ 1x ≥ 200 copies / mL) had significantly higher lymphocyte counts compared to patients without CMV reactivation (n = 85, PCR always < 200 copies / mL). This could be attributed to a significant increase of CD3+ T-lymphocytes while NK- and B-cell numbers did not differ. Within the T-cell compartment, a three-fold expansion of CD8+ T-cells (median 1323 vs. 424 cells / μL, p <0.0001, Mann-Whitney) and an increase in gamma-delta T-cells (median 104 vs. 47 cells / μL, p = 0.0005) was observed, while absolute numbers of CD4+ T-cells did not differ between the groups. This effect was not observed in relation to Epstein-Barr virus (EBV) or Adenovirus (HAdV) reactivation. In multivariate analysis, CD8+ T-cell numbers one year post HSCT were highly influenced by CMV reactivation (p <0.0001, linear regression) but not affected by pre-transplant CMV serostatus of donor (p = 0.22) or recipient (p = 0.14).In a representative subcohort (n = 53, 2008 - 2010), we more closely analyzed the differentiation stages of T-cells based on expression of CD45RA and CCR7. In both the CD4+ and CD8+T-cell subset, the proportion of Effector Memory (EM) and EMRA T-cells was enlarged in patients with (n = 18) compared to patients without (n = 35) early CMV reactivation. In the CD8+ T-cell compartment, this was caused by a major expansion of CD8+ EM and EMRA T-cells (median 485 vs. 141, p <0.0001 and 509 vs. 114 cells / μL, p <0.0001, Figure A), while the Naive (median 105 vs. 169 cells / μL, p = 0.17) and Central Memory (CM) compartment did not differ. In the CD4+ compartment, a non-significant increase of EM and EMRA cells was accompanied by a non-significant decrease of N and CM cells. CMV-specific CD8+ T-cells (median 4.1, range 0.3 - 25.6% of CD8+ T-cells) were detected within the EM and EMRA compartment.Two year after HSCT, data were available for 76 patients. Both in patients with (lymphocyte subsets: n = 34 / T-cell differentiation: n = 12) and without (n = 42 / n = 19) early CMV reactivation, a further reconstitution of CD4+ and CD8+ T-cells was observed, reflected by an expansion of Naive and CM cells (Figure B). However, the total number of CD8+ T-cells decreased in patients with early CMV reactivation, caused by a contraction of late differentiated CD8+ EM and EMRA cells (median 825 to 618, p = 0.0068 and 555 to 378 cells / μL, p = 0.0342, Wilcoxon). ConclusionEarly CMV reactivation leaves a virus-specific and dynamic imprint on the reconstituting immune system 1 and 2 year after HSCT. The marked expansion of CD8 + EM and EMRA T-cells was not seen in patients with early EBV or HAdV reactivation and did not compromise the reconstitution of the Naive and CM compartment available to respond to neo- and recall antigens. Pediatric HSCT recipients differed from solid organ transplantation recipients in which CMV has been correlated to an accelerated and ongoing accumulation of late differentiated T-cells. The dynamic contraction of the CD8+ late differentiated memory T-cell compartment in the second year after HSCT implies that an ongoing process of immune-regulation and further reconstitution is modeling the cellular immune system after discontinuation of immunosuppressive medication.▪ Disclosures:No relevant conflicts of interest to declare.

Kidney and Bladder Outcomes in Children with Hemorrhagic Cystitis and BK Virus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

BK virus (BKV) infection is associated with hemorrhagic cystitis (HC) in hematopoietic stem cell transplantation (HSCT) recipients and nephropathy after kidney transplantation. We assessed the association between BKV and kidney and bladder complications in children developing HC by retrospectively reviewing 221 consecutive pediatric allogeneic HSCT recipients at the Children's Hospital of Philadelphia from 2005 to 2011. We included all patients with BKV PCR testing performed for clinical indication from day 0 until 1 year post-HSCT (N = 68). We assessed the association of any BKV infection (urine and/or blood) or peak BK viremia ≥ 10,000 copies/mL (high viremia) with severe HC (defined as grade IV-bladder catheterization or surgical intervention); the need for dialysis; serum creatinine-estimated glomerular filtration rate at the time of BKV testing, day 100, and day 365; and death. Children with high viremia more likely developed severe HC compared with those with peak viremia < 10,000 copies/mL (21% versus 2%; P = .02). BKV infection of the blood or urine was not associated with the need for dialysis, change in estimated glomerular filtration rate, or mortality. BKV infection is common after pediatric allogeneic HSCT, and plasma testing in those with HC may predict patients who will develop severe bladder injury.

Treatment of BK virus‐associated hemorrhagic cystitis in pediatric hematopoietic stem cell transplant recipients with cidofovir: a single‐center experience

BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is a severe complication after hematopoietic stem cell transplantation (HSCT). Cidofovir (CDV) has emerged as an effective agent for the treatment of BKV nephropathy, but its use for BKV-HC in pediatric HSCT recipients has not yet been established as a standard therapy. We retrospectively investigated the efficacy and safety of CDV therapy for patients with BKV-HC at a single institution and analyzed the clinical management outcomes. From April 2009 to July 2011, 12 patients developed BKV-HC at a median of 37 days after transplant (range 15-59 days). The cumulative incidence was 9% and the median peak of the urine BKV load was 2.5 × 10(10) copies/mL (range 1.4 × 10(9) -1.2 × 10(11) copies/mL). Eleven patients received intravenous CDV (5 mg/kg/dose, with probenecid), whereas 1 patient received CDV (5 mg/kg/dose, without probenecid) intravesically. The median duration of therapy was 25 days (range 9-73 days), and a median of 2 doses was given (range 1-4). A reduction of ≥ 1 log in the BKV load was found in 11 patients, while 1 patient did not have any significant change in BKV load. Clinical improvement was observed in all cases, and no HC-related death was observed. CDV-related toxicity occurred in 1 patient (8%) and spontaneously resolved. CDV appears to be an effective and safe treatment for BKV-HC in pediatric HSCT recipients, but prospective trials are warranted to support its use.

Association of Pre-Transplant Comorbidities with Long-Term Quality of Life (QOL) Among Survivors After Allogeneic Hematopoietic Cell Transplantation (HCT)

s / Biol Blood Marrow Transplant 19 (2013) S150eS166 S153 increasing population of cancer survivors. Much of our knowledge regarding late effects comes from studies in adult recipients or hospital based studies where duration or reliability of follow-up data is limited. The aim of our study was to examine the risk of second malignancy and late mortality in a population-based cohort of pediatric recipients of allogeneic hematopoietic stem cell transplant (HSCT) in Australia. Methods: Australian pediatric allogeneic HSCT recipients aged less than 15 years and treated for a hematological malignancy from 1982-2007, were identified from pediatric hospitals and the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR). Patient records were linked to records held by the Australian Cancer Database (ACD) and National Death Index to determine second cancers and deaths in the cohort. Standardized rates (SIRs & SMRs) and risk factors were characterised for second malignancies following HSCT and late deaths (deaths occurring 2 or more years after HSCT). Results: Second cancers were observed in 17 of the 674 (2.5%) HSCT recipients with a primary cancer diagnosis recorded on the ACD. Thyroid cancer was the most common second cancer observed (n1⁄48) followed by brain tumours (n1⁄44). The rate of second cancers occurring after HSCT was 20 times higher than expected based on rates in the age-, sexand calendar-year matched general population (SIR1⁄420.33, 95% CI1⁄412.64-32). Total body irradiation was associated with a 4-fold increased risk of secondary malignancy, while non-Hodgkin lymphoma patients were 7 times more likely to develop a second malignancy compared to acute lymphoblastic leukaemia patients. While the overall rate of late death was 36 times greater than the rate seen in the age-, sexand calendar-year matched general population (SMR1⁄435.93, 95%CI1⁄426.7448.29), rates of death returned to levels similar to the general population 10 years after HSCT. Conclusions: This is the first study to use population-based registry data to determine the risk of second cancer and late death in pediatric patients with a hematologic cancer treated by allogeneic HSCT. The increased risk of second cancer and late deaths in this population highlights the importance of long-term follow up, surveillance and early detection of second cancer.

Impact of Thymic Function On Chronic Graft-Versus-Host Disease (cGVHD).

Abstract 3052The initial analysis of the impact of cGVHD on thymic function used TREC analysis and demonstrated a sustained decrease in thympoiesis in hematopoietic stem cell transplant (HSCT) recipients with a history of cGVHD (Blood 97:1458, 2011). We have reported that HSCT recipients, who had the clinical resolution of their cGVHD, had increases in their resting regulatory T lymphocytes (rTreg) as compared to HSCT recipients with active cGVHD [ASH 2011]. The increase in rTreg lymphocytes suggested that clinical resolution of cGVHD might be due to improved thymic function, which resulted in the increased production of rTreg lymphocytes.To measure the thymic function of pediatric HSCT recipients with cGVHD, we determined the frequency of recent thymic emigrants (RTE; CD4+, CD45RA+, CD31+) in the whole CD4 T lymphocyte population and the CD4 regulatory T (Treg; CD127-, CD25+) and CD4 conventional T lymphocytes (Tcon; CD127+, CD25+) subpopulations of normal individuals, HSCT recipients without a history of cGVHD (n =16) and HSCT recipients with a history of cGVHD (n=20). The frequency of RTE in total, Treg, and Tcon lymphocytes of the HSCT recipients with cGVHD was decreased (P=0.001) compared to HSCT recipients without a history of cGVHD but was the same as normal individuals. Thus, pediatric HSCT recipients with cGVHD have thymic function that is similar to normal individuals, but have decreased thymic reserves compared to HSCT recipients without cGVHD.However, since rTreg lymphocytes (CD4+, CD127-, CD25+, CD45RA+, FoxP3+) represent only 20% of total Treg lymphocytes, we specifically determined the thymic contribution to rTreg lymphocytes. The RTE content of rTreg lymphocytes was determined in HSCT recipients with active or resolved cGVHD. The RTE content of the rTreg lymphocytes (as a percentage of total CD4 T lymphocytes) was similar in HSCT patients with both active and resolved cGVHD. Thus, the increase in rTreg lymphocytes present in HSCT recipients with the clinical resolution of their cGVHD is not due to an increase in the frequency of RTE in their rTreg lymphocyte population. Therefore, the increase in rTreg lymphocytes, that is associated with the clinical resolution of cGVHD, may be due to either their decreased conversion to Th17 lymphocytes or their decreased apoptosis. Disclosures:No relevant conflicts of interest to declare.

Risk of Bacterial Infection in Pediatric Hematopoietic Stem Cell Transplant Patients Receiving Cephalosporin Prophylaxis

Abstract 4497 Background:At our institution, all hematopoietic stem cell transplant (HSCT) patients receive a prophylactic cephalosporin starting either at Day -1 of transplant or when the absolute neutrophil count (ANC) is below 500 cells/mm3. Cephalosporin prophylaxis continues until neutrophil engraftment (ANC≥500 cells/mm3 for three consecutive days). We sought to determine the incidence of bacterial infections among pediatric recipients of HSCT during the immediate post-transplant period. Methods:This retrospective review examined all HSCT recipients from September 1999 to August 2011. Data collected included gender, age at transplant, diagnosis, type of transplant, graft-versus-host disease and use of radiation. Post-transplant data collected included time to engraftment, antibacterial prophylaxis regimen administered, and number of positive bacterial cultures during post-transplant neutropenia, including organisms isolated and susceptibilities to the prophylactic cephalosporin administered. Patients with primary immune deficiency were excluded from this analysis. To evaluate the effect of prophylaxis we also collected data on all patients with acute myeloid leukemia (AML) at our center during the same time period. AML patients do not receive any prophylactic antibiotics. For AML patients, data collected included gender, age at time of therapy, and number of positive bacterial cultures during post-chemotherapy neutropenia, including organisms isolated and susceptibilities to cephalosporin. Results:A total of 287 stem cell transplant patients with a median age 8.6 years (range 0.4–25) were included. There were 165 (57%) males, 236 (82%) had malignant diseases and 123 (43%) received a total body irradiation based regimen. 71 (25%) received an autologous, and 216 (75%) received allogeneic transplant (78 related, 138 unrelated, 37 cord blood). The median time to engraftment was 17 days (range (8–78). A total of 96 AML patients were included with a median age of 6.6 years (range 0.6–22). The median time of neutropenia was 32 days (range 15–115). The HSCT and AML patients were comparable in age and gender. A total of 36 (13%) transplants were complicated by at least one bacterial infection. The infections (n=57) included 49 gram positive, 7 gram negative, 1 atypical. A total of 35 (36%) chemotherapy cycles were complicated by at least one bacterial infection. A total of 44 infections occurred in the AML patients (36 gram positive, 7 gram negative, 1 atypical). When comparing the two groups, the AML patients had significantly more bacterial infections than the HSCT recipients (P<0.001). Among the HSCT group, using multivariate analysis neither age at transplant, gender, related versus unrelated donor, use of TBI, or use of steroids were associated with increased risk of bacterial infection. However, there was increased risk of bacterial infections in patients with malignant disease (P=0.046). Conclusion:The use of cephalosporin prophylaxis in pediatric HSCT recipients resulted in a lower number of bacterial infections than has been previously reported. HSCT patients had significantly less infections compared to AML patients who received no bacterial prophylaxis. Disclosures:No relevant conflicts of interest to declare.

Metabolic syndrome in patients with hematological diseases

The term metabolic syndrome (MS) defines a clustering of cardiovascular risk factors, formerly known as syndrome X. There is some debate about the diagnostic criteria; but the most widely accepted framework is that defined by the National Cholesterol Education Program Adult Treatment Panel III, which requires the simultaneous occurrence of at least three of abdominal obesity, arterial hypertension, hyperglycemia, hypertrigliceridemia and low high-density lipoprotein cholesterol (HDL-C). The prevalence of MS increases with age and varies depending on genetic factors. An abnormally high prevalence has been observed in patients with heterogeneous conditions, such as solid organ transplant recipients, AIDS patients and long-term cancer survivors. As some of the pathogenetic factors possibly involved include cyclosporine A, corticosteroids and cancer chemoradiotherapy, it is possible that MS may also be a complication in hematological patients. Some of the characteristics of MS have been reported with a certain frequency in thalassemia patients, and are mainly attributed to iron overload. Impaired hemostasis is a feature of MS rather than a factor predisposing to its development. In oncohematology, an abnormally high prevalence of MS features has been observed in survivors of pediatric acute lymphoblastic leukemia. In addition to corticosteroid- and cancer therapy-related hypogonadism, hypothyroidism and defective growth hormone incretion are other factors related to the development of MS. Moreover, the highest frequency of MS is observed in hematopoietic stem cell transplantation (HSCT) recipients. Pediatric patients and allogeneic HSCT recipients have been the subject of foremost investigations; but adult patients and autologous HSCT recipients have also been studied more recently. A wide range of factors may contribute to the development of MS in HSCT recipients. Unfortunately, the real entity of the problem is far from clear because of the retrospective design of the studies, the limited size of their populations and their heterogeneous selection criteria, thus making it difficult to determine whether MS is a transient and possibly reversible phenomenon or a true late effect of the procedure.

Norovirus Infection in Pediatric Hematopoietic Stem Cell Transplantation Recipients: Incidence, Risk Factors, and Outcome

Norovirus infections are increasingly being recognized as important causes of diarrhea in hematopoietic stem cell transplantation (HSCT) recipients. This retrospective study aimed to evaluate the cumulative incidence, risk factors, and outcomes of norovirus infection in pediatric HSCT recipients. Among 55 patients age <21 years who underwent first HSCT between July 2007 and June 2011, 49 patients developed diarrhea and had stool tested for norovirus. Eight of these patients were found to be infected with norovirus. All were sporadic cases and manifested with nausea, vomiting, and diarrhea. The median age of these patients was 5.2 years (range, 0.5-18.5 years). Six were males. Seven patients underwent unrelated donor HSCT, and 1 patient underwent autologous cord blood HSCT. Two patients had norovirus infection before HSCT that persisted after transplantation. In the remaining 6 patients, norovirus developed at a median of 36.5 days posttransplantation (range, 5-517 days). The cumulative incidence of norovirus infection was 12.9% at 2 years posttransplantation. Risk factors for norovirus infection included the use of peripheral blood or cord blood as the stem cell source (P = .043) and administration of fludarabine (P = .002) and alemtuzumab (P = .011). The median time to viral clearance was 145 days (range, 13-263 days). Four-year survival was similar in norovirus-infected patients and noninfected patients (56.3% versus 58.3%).

Diagnostic Utility of Human Cytomegalovirus-Specific T-Cell Response Monitoring in Predicting Viremia in Pediatric Allogeneic Stem-Cell Transplant Patients

Several studies proved that virus-specific T-cells play a pivotal role in controlling cytomegalovirus (CMV) infection in adult allogeneic hematopoietic stem-cell transplant (HSCT) patients. Fewer data are available in pediatric HSCT settings, when immature and inexperienced immune system may affect antiviral immune reconstitution. We analyzed prospectively the CMV-specific T-cell reconstitution in a cohort of 31 pediatric allogeneic HSCT recipients at 30, 60, 90, 120, 180, and 360 days after HSCT. Depending on donor-recipient CMV serostatus, we observed distinct patterns and kinetics of CMV-specific T-cell immune reconstitution: during the early time-points, patients displayed a severe reduction in CMV-specific T-cell recovery in both CMV seropositive donor (D+) group and CMV seronegative donor (D-) on CMV seropositive recipients (R+). From day 90 onward, statistical significant differences in the profile of T-cell immune reconstitution emerged between D+ and D-. The pattern of immune reconstitution was characterized by heterogeneous kinetics and efficiencies: we report cases of: (1) spontaneous antiviral T-cell recovery with no previous viremia, (2) immune T-cell recovery anticipated by CMV viremia, and (3) no T-cell immune reconstitution despite previous viremia episodes. Given the heterogeneous scenarios of antiviral T-cell immune recovery in pediatric allogeneic HSCT, we conclude that the evaluation of the antiviral immune reconstitution is a promising and appealing system for identifying patients at higher risk of CMV infection. The use of interferon-γ ELISPOT test is a valid tool for immunological monitoring and predicting CMV viremia in pediatric HSCT.

Respiratory viral infections during the first 28 days after transplantation in pediatric hematopoietic stem cell transplant recipients

Respiratory viruses (RVs) are a known cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). In this retrospective study, we focused on the first 28 d after transplantation in pediatric HSCT recipients and showed that a multiplex PCR assay significantly increased RV detection compared with a viral culture method. Among 176 pediatric HSCT recipients, 84 with respiratory symptoms within one yr after HSCT were tested by viral culture or multiplex PCR. Within 28 d after HSCT, nine patients were infected with RVs; the incidence of a first episode of RV infection within 28 d after HSCT was 5.1%. Eight patients recovered without complications. However, one patient died of adenovirus (AdV) pneumonia with pulmonary hemorrhage; the mortality rate of RV infection within 28 d after HSCT was 0.57%. In the nine patients with RV infection, five different types of RV were identified, either alone or with another RV. These were corona virus (CoV), rhinovirus (RhV) and respiratory syncytial virus combined with CoV; AdV combined with RhV; and parainfluenza virus. Viral culture detected only one case of RV infection, while multiplex PCR detected eight, suggesting that screening of respiratory infections using multiplex PCR is better than the conventional culture method.