Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children's Oncology Group Report.

Optimal therapy for posttransplant lymphoproliferative disease (PTLD) remains problematic. A phase II trial adding rituximab to a low-dose cyclophosphamide and prednisone regimen was conducted for pediatric patients with Epstein-Barr virus (EBV) (+), CD20 (+) PTLD. Fifty-five patients were enrolled. Toxicity was similar for cycles of therapy containing rituximab versus those without. The complete remission (CR) rate was 69% (95% confidence interval (CI); 57%-84%). Of 12 patients with radiographic evidence of persistent disease at the end of therapy, eight were in CR 28 weeks later without further PTLD therapy. There were 10 deaths, 3 due to infections while receiving therapy and 7 from PTLD. The 2-year event-free survival (alive with functioning original allograft and no PTLD) was 71% (95% CI: 57%-82%) and overall survival was 83% (95% CI: 69%-91%) with median follow-up of 4.8 years. Due to small numbers, we were unable to determine significance of tumor histology, stage of disease, allograft type or early response to treatment on outcome. These data suggest rituximab combined with low-dose chemotherapy is safe and effective in treating pediatric with EBV (+) PTLD following solid-organ transplantation.

Unrelated donor hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis.

We report outcomes after unrelated donor hematopoietic cell transplantation (HCT) for 91 patients with hemophagocytic lymphohistiocytosis (HLH) transplanted in the US in 1989-2005. Fifty-one percent were <1 year at HCT and 29% had Lansky performance scores<90%. Most (80%) were conditioned with BU, CY, and etoposide (VP16) with or without anti-thymocyte globulin. Bone marrow was the predominant graft source. Neutrophil recovery was 91% at day-42. The probabilities of grades 2-4 acute GVHD at day-100 and chronic GVHD at 5 years were 41 and 23%, respectively. The overall mortality rate was higher in patients who did not receive BU/CY/VP16-conditioning regimen (RR 1.95, P=0.035). The 5-year probability of overall survival was 53% in patients who received BU/CY/VP16 compared to 24% in those who received other regimens. In the subset of patients with known disease-specific characteristics, only one of five patients with active disease at HCT is alive. For those in clinical remission at HCT (n=46), the 5-year probability of overall survival was 49%. Early mortality rates after HCT were high, 35% at day-100. These data demonstrate that a BU/CY/VP16-conditioning regimen provides cure in approximately 50% of patients and future studies should explore strategies to lower early mortality.

Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents.

PURPOSE: To determine the treatment outcome and clinical factors that are of prognostic significance for children and adolescents with relapsed or refractory Hodgkin's disease (HD) who received treatment with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT). PATIENTS AND METHODS: Fifty-three consecutive children and adolescents 21 years of age or younger with relapsed or refractory HD underwent HSCT. RESULTS: At day 100 after transplantation, 29 patients (55%) were in a complete remission or maintained a continuous complete response, six (11%) had a partial response, and 11 (21%) failed to respond or had progressive disease. The failure-free survival (FFS) at 5 years was 31%, and overall survival was 43%. Twenty-one patients died of progressive HD, and nine died secondary to transplantation-related complications, including two secondary leukemias. Prognostic factors important for FFS were normal pretransplantation lactate dehydrogenase levels (5-year FFS = 42%), compared with patients with elevated LDH levels (5-year FFS = 0%) (P < .001), and disease sensitivity at the time of HSCT with FFS in untreated relapse, sensitive disease, and resistant disease 44%, 35%, and 9%, respectively (P = .06). There was no statistically significant difference in FFS or overall survival between age subgroups that were analyzed (< 13, 13 to 18, 19 to 21) or in comparison with an adult cohort. CONCLUSION: HSCT is an effective treatment modality that can result in long-term cures and should be considered for children and adolescents with relapsed HD.

Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies.

PURPOSE: To compare hematopoietic recovery, duration of hospitalization, and 100-day survival in patients who received allogeneic-blood stem cells (BSC) or conventional allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: From December 1994 to August 1995, 21 patients participated in a phase II study of allogeneic BSC transplantation. Cells mobilized with granulocyte colony-stimulating factor (G-CSF; 5 micrograms/kg/ d) were collected from human leukocyte antigen (HLA)-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. G-CSF (10 micrograms/kg/d) was administered posttransplant. The outcomes were compared with 22 identically treated historical patients who received allogeneic BMT. RESULTS: The median infused CD34+ cell and granulocyte-macrophage colony-forming unit (CFU-GM) content were 7.73 x 10(4)/kg and 41.6 x 10(4)/kg, respectively. The median time to a neutrophil count greater than 500/ microL was 11 days after BSC and 16.5 days after BMT (P = .0003). A trend toward faster platelet and RBC recovery after BSC was observed. BSC patients received fewer platelet transfusions: 10 versus 19 (P = .015). The median length of hospitalization was shorter after BSC transplantation: 25 versus 31.5 days (P = .0243). The 100-day survival rates were similar: 83% after BSC and 75% after BMT (P = .3585). The incidence of acute GVHD grade II to IV was 57% and 45% for BSC and BMT, respectively (P = .4654). CONCLUSION: In comparison to BMT, allogeneic BSC transplantation may result in faster hematopoietic recovery, shorter hospital stay, and similar early survival. Whether allogeneic BSC are superior to bone marrow needs to be determined in randomized trials.

Allogeneic stem cell transplantation in X-linked lymphoproliferative disease: two cases in one family and review of the literature.

X-linked lymphoproliferative disease (XLP) is a rare immunodeficiency caused by mutations in the signaling lymphocyte activating molecule-associated protein/SH2D1A gene and characterized by a dysregulated immune response to Epstein-Barr virus and other pathogens. The clinical presentation is heterogeneous and includes fulminant infectious mononucleosis, lymphoma, hypogammaglobulinemia and aplastic anemia. XLP is associated with a high morbidity and overall outcome is poor. At present, allogeneic stem cell transplantation (alloSCT) is the only curative treatment. XLP patients may be recognized in various stages of disease and even when symptoms are not yet evident. We here present two related XLP patients in different stages of disease that were both treated successfully with alloSCT using a matched unrelated donor. In addition, we have reviewed all reported cases of alloSCTs in XLP patients. Based on these results and in order to improve the final outcome, we conclude that alloSCT should be recommended in both symptomatic and asymptomatic XLP patients.

Posttransplant lymphoproliferative disorder: significance of central nervous system involvement.

BACKGROUND: Few data exist regarding central nervous system (CNS) involvement in patients with posttransplant lymphoproliferative disorder (PTLD). The purpose of this study was to review the Israel Penn International Transplant Tumor Registry (IPITTR) experience with CNS involvement by PTLD. METHODS: Nine hundred ten PTLD cases from the United States were reported to the IPITTR and reviewed for CNS involvement. RESULTS: One hundred thirty-six transplant recipients with PTLD (15%) had CNS involvement. The highest incidence of CNS involvement occurred in pancreas (3 of 11; 27%) and kidney transplant recipients (76 of 429; 18%). Fifteen cases occurred in children and 121 cases in adults. For both children and adults, isolated CNS disease was associated with better survival when compared with multiple-site involvement (children: 29% vs 0%; adults: 12% vs 6%; P < .05). Three-year survival in PTLD patients with CNS involvement was 9.4% and without CNS involvement was 49.4% (P < .01). Radiation therapy alone appeared to provide the best survival rates (25%). CONCLUSIONS: CNS involvement in transplant recipients with PTLD carries an ominous prognosis; however, isolated CNS involvement has a better prognosis than CNS plus extracranial involvement. Radiation therapy alone provides the best results, but this may be a reflection of isolated CNS disease.

Chemotherapy for posttransplant lymphoproliferative disorder: the Israel Penn International Transplant Tumor Registry experience.

INTRODUCTION: Very little published data exist regarding the results of chemotherapy treatment of posttransplant lymphoproliferative disorder (PTLD). The purpose of the study was to review the Israel Penn International Transplant Tumor Registry experience with PTLD treated with chemotherapy. METHODS: Patients with PTLD who received chemotherapy were identified and data collected regarding demographics, tumor characteristics, recurrence rates, and survival. RESULTS: One hundred ninety three solid organ transplant recipients with PTLD who received chemotherapy were identified. Most patients were male (142:51) and Caucasian (148; 16 AA, 29 unspecified). Most PTLD were B-cell predominant (81%), monoclonal (71), and CD 20+ (60% of patients tested). Organ transplanted included: kidney, 92 (48%); heart, 54 (28%); liver, 30 (16%); pancreas, 8 (4%); and lung, 9 (5%). Median time to presentation posttransplant was 24.5 months (range 0.8 to 226.5 months). Ninety patients received CHOP, 12 ProMACE, 65 other multidrug regimens, and 23 patients received single-agent chemotherapy. Five-year survival for these four regimens were: 24%, 25%, 32%, and 5%. PTLD-specific death rates were 34%, 34%, 40%, and 48%. CONCLUSIONS: Single-agent chemotherapy appears to be inferior to other chemotherapy regimens for PTLD as it is associated with lower survival.

Prostate cancer prior to solid organ transplantation: the Israel Penn International Transplant Tumor Registry experience.

INTRODUCTION: Prostate adenocarcinoma (PCA) is the second leading cause of cancer-related deaths in men, and with routine prostrate specific antigen (PSA) screening, is being diagnosed with increasing frequency. To date, reported experiences with transplantation in men with a history of PCA are limited to only a few patients. This study presents the first series of transplant recipients with a history of PCA. METHODS: Analysis of transplant recipients with a history of pretransplant PCA was performed on the Israel Penn International Transplant Tumor Registry database. PCA were staged using American Joint Committee on Cancer criteria. Statistics analysis was performed by chi-square and Student t tests. RESULTS: Ninety patients with preexisting PCA were identified: 77 renal, 10 heart, and three liver transplant recipients. Mean age at PCA diagnosis was 61.3 +/- 6.3 years. Median interval between diagnosis and transplantation was 19.3 months, and median follow-up after transplantation was 20.5 months. Median time to PCA recurrence was 10.6 months after transplantation and median survival time with recurrent PCA was 49.2 months after transplant. Patient mortality was 28.8%, and PCA-related death rate was 7.8%. PCA recurrence rate was 17.7%. Tumor recurrence rates in stage I and II disease (14 and 16%) were lower than in stage III disease (36%). CONCLUSIONS: In conclusion, death rate to disease other than PCA is three times that due to PCA. PCA recurrence rates are relatively low in patients who initially presented with stage I and II disease, and are half that of patients with stage III disease.

Depletion of EBV-infected cells in donor marrow by counterflow elutriation.

Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disease (PTLD) is a well-recognized complication of T cell-depleted (TCD) allogeneic bone marrow transplantation (BMT). Certain methods of TCD, such as counterflow elutriation (CE), have not been associated with an increased incidence of PTLD. Since CE depletes B cells as well as T cells, the hypothesis that CE depletes donor marrow of EBV-infected cells was tested in this study. Marrow samples from 70 donors were assayed by qualitative and semi-quantitative polymerase chain reaction (PCR) amplification to detect EBV DNA in four cellular fractions produced by elutriation: a small cell fraction (F70), two intermediate-sized cell fractions (F110 and F140), and a large cell (hematopoietic precursor-enriched, lymphocyte-depleted) rotor-off (R/O) fraction. The distribution of B cells in elutriation fractions was 21% (F70), 59% (F110), 18% (F140), and 2% (R/O). Qualitatively, the frequency of EBV DNA detected in fractions was 49% (F70), 57% (F110), 73% (F140), and 44% (R/O). The relative concentration of EBV DNA in each fraction was determined by semiquantitative PCR. The mean number of EBV DNA copies per 150,000 cells was 0.57 (F70), 4.6 (F110), 5.7 (F140), and 0.61 (R/O). Relative EBV DNA load in each fraction was calculated by multiplying the mean concentration of EBV DNA per fraction and mean mononuclear cell content in each fraction. The relative distribution of EBV DNA was 0.5, 58, 40, and 1.5% in the F70, F110, F140, and R/O fractions, respectively. No correlation between the amount of EBV in the graft and development of PTLD could be made, because only one of the 70 recipients developed PTLD and this was following autologous hematopoietic recovery. Although these results demonstrate that the majority of EBV-infected cells in marrow are separated from the TCD graft by counterflow elutriation, further studies are required to differentiate the role of this phenomenon from that of other potential factors, such as the amount of T cell depletion and recovery of EBV immunity in the pathogenesis of PTLD after BMT.

Antitumor activity of human umbilical cord blood cells: A comparative analysis with peripheral blood and bone marrow cells.

Although the hematopoietic reconstituting ability of human umbilical cord blood cells (UCBC) is well documented, their antitumor cytotoxic potential has not been well studied. Therefore, UCBC were compared to normal peripheral blood stem cells (PBSC) and bone marrow (BM) stem cell harvests for cytomorphology, antitumor cytotoxic activity before and after ex vivo cytokine manipulation, response to T and B cell mitogens, expression of adhesion molecules and immunophenotypes using flow cytometry, cytokine production and in vivo antitumor activity. BM and PBSC, but not UCBC, did not form cellular clusters in culture. More cytotoxic granules were present in the cytoplasm of UCBC than PBSC following activation in vitro. Ex vivo manipulation of UCBC with cytokines produced more cytotoxicity to K562 and Raji tumor cells than PBSC or BM (p<0.001). Most cytotoxic cells in UCBC cultures were T lymphocytes, and a correlation existed between the number of CD56+ cells and cytotoxicity levels, particularly after in vitro activation with interleukin-2. No significant difference in adhesion molecule expression was noted among UCBC, PBSC and BM cells. However, there was a significantly decreased expression of CD54 molecules (ICAM) on UCBC compared to PBSC (p<0.05). IL-2 activated UCBC showed significant antitumor effects against K562 leukemic cells grown in SCID mice. Thus UCBC contained more antitumor effector cells and precursors than cells from marrow or peripheral blood cells which might be capable of providing a therapeutic effect.

Fatal eosinophilic disease following autologous bone marrow transplantation.

A 15-year-old girl developed massive, fatal eosinophilic disease following autologous bone marrow transplantation (BMT) for Hodgkin's disease (HD). Prior to autologous BMT, the erythrocyte sedimentation rate (ESR) was elevated, with active HD, but eosinophilia was absent. Post-autologous BMT, ESR and peripheral eosinophilia were observed to correlate with respiratory symptoms. Initial evaluation revealed no recurrent tumor, infection or other identifiable etiology. A diagnosis of chronic eosinophilic pneumonia was made following lung biopsy. A complete response was initially achieved with steroid therapy; however, when steroid therapy was tapered, the eosinophilia and elevated ESR recurred with worsening respiratory symptoms. Terminally, severe pulmonary disease developed and recurrent HD was found in lung, lymph nodes and bone marrow. During episodes of eosinophilia, the patient's serum stimulated her bone marrow as well as control marrow to produce predominantly eosinophilic colonies. Eosinophilic colony production was not observed with patient's sera obtained prior to or during autologous BMT or with control sera. This patient died of eosinophilic inflammatory disease following autologous BMT. The etiology of this disease was not definitely identified but appeared to be due to an eosinophilic-stimulating factor which developed after autologous BMT.

Cyclosphosphamide/prednisone for combination immunosuppression and therapy of lymphoproliferative disease.

Post-transplant lymphoproliferative disease (PTLD) is a well-known complication of solid organ transplantation. While this disorder can often be controlled by decreasing immunosuppression, it is frequently difficult to control the resultant rejection. This case exemplifies this dilemma. To solve this problem, cyclosphosphamide (600 mg/m2) and prednisone (2 mg/kg times 5 days) were given every 3 weeks to simultaneously treat PTLD and provide immunosuppression.

B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: risk factors, treatment and outcome.

Twenty-six cases of B cell lymphoproliferative disorder (BLPD) were identified among 2395 patients following hematopoietic stem cell transplants (HSCT) for which an overall incidence of BLPD was 1.2%. The true incidence was probably higher, since 9/26 of the diagnoses were made at autopsy. No BLPD was observed following autologous HSCT, so risk factor analyses were confined to the 1542 allogeneic HSCT. Factors assessed were HLA-mismatching (> or = 1 antigen), T cell depletion (TCD), presence of acute GvHD (grades II-IV), donor type (related vs unrelated), age of recipient and donor, and underlying disease. Factors found to be statistically significant included patients transplanted for immune deficiency and CML, donor age > or = 18 years, TCD, and HLA-mismatching, with recipients of combined TCD and HLA-mismatched grafts having the highest incidence. Factors found to be statistically significant in a multiple regression analysis were TCD, donor age and immune deficiency, although 7/8 of the patients with immunodeficiencies and BLPD received a TCD graft from a haploidentical parent. The overall mortality was 92% (24/26). One patient had a spontaneous remission, but subsequently died >1 year later of chronic GVHD. Thirteen patients received therapy for BLPD. Three patients received lymphocyte infusions without response. The only patients with responses and longterm survival received alpha interferon (alphaIFN). Of seven patients treated with alphaIFN there were four responses (one partial and three complete). These data demonstrate that alphaIFN can be an effective agent against BLPD following HSCT, if a timely diagnosis is made.

Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry.

Seven male patients in the David T Purtilo International X-linked Lymphoproliferative Disease (XLP) Registry have undergone allogeneic hematopoietic stem cell transplantation (HSCT). All patients received HSCT from HLA-identical donors: sibling BM, five; unrelated BM, one; and sibling umbilical cord blood, one. Ages at time of HSCT ranged from 5 to 30 years. Pre-HSCT clinical course varied, but four boys had a significant history of chronic and/or serious infections. Conditioning regimens varied: TBI containing regimens, four, chemotherapy only, three. All patients engrafted. Six developed grade I-II acute GVHD but no chronic GVHD. Four are alive and well with normal immune function greater than 3 years following HSCT. Three died within 100 days: disseminated adenovirus, one; polymicrobial sepsis, one; and multiple organ system failure and bleeding diathesis, one. No EBV-associated post-transplant complications were observed, even though all donors except the umbilical cord blood were EBV-seropositive. Unsuccessful HSCT was associated with age at HSCT (> 15 years), TBI-containing regimen and significant history for pre-HSCT infections. These results provide evidence that HSCT performed during childhood with HLA-identical sibling donors, regardless of EBV serostatus, offers the only curative therapy for XLP.

Immunologic phenotype and function in human bone marrow, blood stem cells and umbilical cord blood.

The T cell-mediated antineoplastic activity observed following allogeneic transplantation and the suggestion of improved therapeutic efficacy by autologous peripheral stem cell transplantation (PSCT) as compared to autologous bone marrow transplantation (ABMT) for non-Hodgkin's lymphoma (NHL) stimulated our interest in the immunologic competence of stem cell products. We report the immune phenotype and function of normal peripheral blood (PB) cells, bone marrow (BM) cells from normal donors and cancer bearing patients, GM-CSF-mobilized and apheresed blood mononuclear cells from NHL patients, unmobilized apheresed mononuclear cells from normal volunteers and umbilical cord blood (CB). The analyses include three-color fluorescent cytometry of the major hematologic and immunologic phenotypes as well as natural killer (NK) activity, natural suppressor (NS) activity, and phytohemagglutinin (PHA) and pokeweed (PWM) mitogenesis. These studies demonstrated an increased frequency of T cells in apheresis products as compared to BM and CB products. Specifically, the mobilized PSC had significant increases in CD3+, CD4+, CD45RO+ and CD56+ cells relative to BM cells. In addition, the frequency of TCR gamma/delta + cells in all the stem cell products, with the exception of CB, were also increased compared to normal peripheral blood leukocytes (PBL). However, all the stem cell products had a significant depression in T (PHA mitogenesis) and B (PWM mitogenesis) cell function. The depression in immune cell functionality, in the PSC products was perhaps due to the high frequency of monocytes which appeared to be increased due to both mobilization and apheresis. The frequency of the NK cell phenotype (CD56) but not function was increased in the mobilized PSC products, while the NK cell function in the BM products from cancer patients but not normal donors was depressed as compared to normal PBL. In summary, there are significant differences in the cellular phenotypes and immunologic competence among the various stem cell products with potential therapeutic implications.

Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies.

Forty-one patients were studied at set times after allogeneic blood stem cell transplantation (alloBSCT) for recovery of lymphocyte numbers and function. Cells were mobilized with G-CSF from HLA-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate; G-CSF was administered post-transplant. Median time to absolute lymphocyte count (ALC) >500/microl was 17 days vs 41 and 49 days in historical alloBMT patients with G-CSF (n = 23) or no cytokine (n = 29) post-transplant, respectively (P < 0.0001). CD4/CD8+ ratio was 1.9 on day 28 after alloBSCT, then gradually declined to 0.8 at 1 year due to more rapid CD8+ cell recovery. Mean phytohemagglutinin-induced T cell responses were lower than normal on day +28 (P < 0.05), then tended to recover towards normal values. Natural-killer cytotoxicity remained low from day +28 to 1 year post-alloBSCT, but considerable lymphokine-activated killer cytotoxicity was induced from cells already obtained on day +28. Faster lymphocyte recovery correlated with better survival in alloBSCT patients (median follow-up 287 days, P = 0.002), ALC recovery was not affected by acute GVHD, CMV infections or doses of infused cells. ALC recovery did not correlate with survival in either historical alloBMT group. These data suggest that after alloBSCT lymphocyte reconstitution is faster than after alloBMT, and that quicker lymphocyte recovery predicts better survival in the alloBSCT setting.

Pediatric hematopoietic stem cell transplantation.

The successful use of allogeneic HSCT for children with malignant and nonmalignant diseases continues to be limited by the development of acute and chronic GVHD, infectious complications, delayed recovery of the immune system, acute and long-term toxicity, and relapse of disease. Significant advances have been made, particularly in the ability to identify suitable sources of HSC. Future advances will depend on a better understanding of the biology of HSC sources, GVHD, immune reconstitution, and common complications. Improved therapies are dependent on participation of children in well-designed, translational and clinical transplant studies.

A review of Epstein-Barr virus infection in patients with immunodeficiency disorders.

Epstein-Barr virus (EBV), one of 8 known human herpesviruses, infects the vast majority of mankind and infections are generally subclinical. However, EBV infection has been associated with a spectrum of diseases, lymphoproliferative diseases (EBV-LPD) in particular, including malignant lymphoma. EBV-LPD are frequently observed in patients with primary or secondary immunodeficiencies. The incidence of EBV-LPD is on the rise, partly because of increasing numbers and success of hematopoietic stem cell and solid organ transplants and partly because many patients with immunodeficiencies, both primary and secondary, including AIDS, live longer, with improvements in supportive care. Herein, a spectrum of EBV-associated diseases in patients with immunodeficiency are summarized and discussed mainly focusing on their pathogenetic mechanism(s).

Second malignancies after autologous hematopoietic cell transplantation in children.

Childhood autologous hematopoietic cell transplant (auto-HCT) survivors can be at risk for secondary malignant neoplasms (SMNs). We assembled a cohort of 1487 pediatric auto-HCT recipients to investigate the incidence and risk factors for SMNs. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), central nervous system tumors (14%) and Wilms tumor (2%). Median follow-up was 8 years (range, <1-21 years). SMNs were reported in 35 patients (AML/myelodysplastic syndrome (MDS)=13, solid cancers=20, subtype missing=2). The overall cumulative incidence of SMNs at 10 years from auto-HCT was 2.60% (AML/MDS=1.06%, solid tumors=1.30%). We found no association between SMNs risk and age, gender, diagnosis, disease status, time since diagnosis or use of TBI or etoposide as part of conditioning. OS at 5-years from diagnosis of SMNs was 33% (95% confidence interval (CI), 16-52%). When compared with age- and gender-matched general population, auto-HCT recipients had 24 times higher risks of developing SMNs (95% CI, 16.0-33.0). Notable SMN sites included bone (N=5 SMNs, observed (O)/expected (E)=81), thyroid (N=5, O/E=53), breast (N=2, O/E=93), soft tissue (N=2, O/E=34), AML (N=6, O/E=266) and MDS (N=7, O/E=6603). Risks of SMNs increased with longer follow-up from auto-HCT. Pediatric auto-HCT recipients are at considerably increased risk for SMNs and need life-long surveillance for SMNs.

Twice daily i.v. bolus tacrolimus infusion for GVHD prophylaxis in children undergoing stem cell transplantation.

Tacrolimus is routinely administered for GVHD prophylaxis as a 24-h continuous infusion that requires a dedicated i.v. line and thus becomes logistically difficult to administer, especially in young pediatric patients. We investigated the safety and efficacy of twice daily bolus infusions of i.v. tacrolimus in 33 children undergoing hematopoietic stem cell transplantation (HSCT) at our institution. Tacrolimus was started at an initial dose of 0.015 mg/kg i.v. bolus administered as a 2-h infusion and then given at every 12 h to maintain a trough drug level between 5-15 ng/mL. Patients also received short-course MTX (66%) or mycophenolate mofetil (34%) in combination with tacrolimus. No acute infusional toxicities were observed with bolus infusions of i.v. tacrolimus. Nephrotoxicity occurred in 14/33 (42%) patients and 48% developed hypertension (HT). Almost all (94%) patients required magnesium supplements to maintain magnesium (Mg) levels 1.5 mg/dL. In all, 3 (9%) patients developed severe sinusoidal obstruction syndrome (SOS). One patient developed posterior reversible leuko-encephalopathy syndrome (PRES) and one additional patient had tremors. The prevelance of these side-effects was similar to those reported for continuous i.v. administration. In all, 28% of the evaluable patients developed acute GVHDgrade II, though the incidence of severe (grade III-IV) GVHD was only 7%. These results suggest that intermittent bolus i.v. tacrolimus administration is a safe and effective method of GVHD prophylaxis in children.