Reduced-toxicity conditioning regimen with busulfan, fludarabine, rATG, and 400 cGy TBI in pediatric patients undergoing hematopoietic stem cell transplant for high-risk hematologic malignancies.

BACKGROUND: Myeloablative conditioning regimens decrease the risk of relapse in pediatric patients undergoing allogeneic hematopoietic stem cell transplant (HCT) for hematologic malignancies, but cause significant toxicities PROCEDURE: This prospective study evaluated the use of a reduced-toxicity, myeloablative regimen with dose-adjusted busulfan, fludarabine, antithymocyte globulin and 400 cGy of total body irradiation in 40 patients < 21 years of age undergoing HCT for high-risk leukemias. Busulfan pharmacokinetics were measured to target 4000 µmol*min/day in the first 30 patients; this was increased to 5000 µmol*min/day in the subsequent 10 in efforts to further decrease relapse risk RESULTS: Overall survival at two- and five-years post-HCT was 67% and 51%, respectively. Relapse occurred in 11 patients (28%) at a median of seven months and was the leading cause of death. Transplant-related mortality was 8% and 13% at 100 days and one-year post-HCT, respectively. Trends toward improved survival were seen in patients transplanted for myeloid disease using bone marrow as stem cell source who achieved a busulfan AUC > 4000 µmol*min/day with two-year relapse-free survival approaching 80% CONCLUSIONS: This conditioning regimen is safe and effective in patients with high-risk leukemias, particularly myeloid disease. Larger studies are needed to compare its safety and efficacy to other myeloablative regimens in this population.

Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant: Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression.

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

High-dose chemotherapy and autologous hematopoietic stem-cell rescue for treatment of relapsed and refractory Wilms tumor: Re-evaluating outcomes.

Wilms tumor (WT) treatment regimens are curative for more than 80% of patients, but those with relapsed or refractory disease continue to have poor outcomes. High-dose chemotherapy followed by autologous stem cell rescue is often utilized although outcomes remain variable. We report on HD-ASCR outcomes in 24 patients with relapsed or refractory Wilms tumor. Three-year disease free and overall survival are 46% and 60%, respectively, which is similar to those reported for conventional salvage therapies. These outcomes suggest that conventional salvage therapies should be employed for relapsed and refractory WT rather than HD-ASCR.

Early mixed T-cell chimerism is predictive of pediatric AML or MDS relapse after hematopoietic stem cell transplant.

Patients with acute myeloid leukemia (AML) who relapse after hematopoietic stem cell transplantation (HCT) have dismal outcomes. Our ability to predict those at risk for relapse is limited. We examined chimerism trends post-HCT in 63 children who underwent HCT for AML or myelodysplastic syndrome (MDS). Mixed T-cell chimerism at engraftment and absence of chronic graft versus host disease (cGVHD) were associated with relapse (P = 0.04 and P = 0.02, respectively). Mixed T-cell chimerism at engraftment was predictive in patients without cGVHD (P = 0.03). Patients with engraftment mixed T-cell chimerism may warrant closer disease monitoring and consideration for early intervention.

The Impact of High-resolution HLA-A, HLA-B, HLA-C, and HLA-DRB1 on Transplant-related Outcomes in Single-unit Umbilical Cord Blood Transplantation in Pediatric Patients.

Current practice for selecting donor units for umbilical cord blood transplant (UCBT) involves matching at HLA-A and HLA-B by low-resolution typing and the HLA-DRB1 allele by high-resolution (HR) typing. We retrospectively studied the impact of HR allele matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1 on transplant-related outcomes in 60 single-unit UCBTs in pediatric patients with malignant and nonmalignant conditions. Five-year overall survival of our cohort was 71% (95% confidence interval, 58-81); 27% experienced primary graft failure. Applying HR typing, donor-recipient mismatch variability increased ranging from 1/8 to 8/8, however, no impact on primary graft failure, graft-versus-host disease or posttransplant infection was observed. UCBTs with ≥6/8 HR matches did have a better overall survival (P=0.04) and decreased transplant-related mortality (P=0.02) compared with <6/8 HR matches. Using standard HLA typing, we showed an increased incidence of acute graft-versus-host disease (grade II to IV) and decreased transplant-related mortality in comparing the matched (6/6) versus ≤5/6 group (P=0.05 and 0.05, respectively). These data support the use of current guidelines for umbilical cord blood selection and encourage utilization of HR typing to select umbilical cord blood units matched at ≥6/8 especially when appropriate ≥5/6 units are available.

Safety, Pharmacokinetics, and Efficacy of Palifermin in Children and Adolescents with Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplantation: A Pediatric Blood and Marrow Transplant Consortium Trial.

Currently, effective pharmacologic treatment to reduce severe oral mucositis (OM) resulting from high-dose myeloablative cytotoxic therapy in the pediatric population is not available. Palifermin has been proven to decrease the incidence and duration of severe OM in adults with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, however, data on palifermin treatment are limited. A phase I dose-escalation study of palifermin in pediatric patients with acute leukemias undergoing myeloablative HSCT with total body irradiation, etoposide, and cyclophosphamide was performed to determine a safe and tolerable dose and to characterize the pharmacokinetic (PK) profile and efficacy of palifermin. Twenty-seven patients in 3 age groups (1 to 2, 3 to 11, and 12 to 16 years) and 3 dose levels (40, 60, and 80 µg/kg/day) were studied. There were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population. PK data showed no differences between the 3 age groups. Exposure did not increase with increase in dose. The maximum severity of OM (WHO grade 4) occurred in 6 patients (22%), none of whom was in the 80-µg/kg/day dosing group. This study showed that all doses were well tolerated and a good safety profile in all 3 pediatric age groups was seen.

Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation.

Busulfan (Bu) is widely used in conditioning regimens for infants undergoing allogeneic hematopoietic progenitor cell transplantation (HPCT), but the best approach to administer Bu in this population is still unknown. Here, we report a single-center experience of the use of a test dose to guide dose adjustment of intravenous (i.v.) Bu therapy in infants. Between 2004 and 2013, 33 infants younger than 1 year with nonmalignant conditions received allogeneic peripheral blood or cord blood HPCT after a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, antithymocyte globulin, and 2 single daily doses of i.v. Bu. Pharmacokinetic results of a test dose of i.v. Bu (.8 mg/kg) were used to determine the dose of 2 single daily i.v. Bu regimen doses, adjusted to target an area under the curve (AUC) of 4000 µMol*minute per day in a first cohort (n = 12) and 5000 µMol*minute in a second cohort (n = 21). The mean Bu clearance in our infant patients was found to be 3.67 ± 1.03 mL/minute/kg, and the test dose clearance was highly predictive of the regimen dose clearance. The mean AUC achieved after the first single daily regimen dose was 3951 ± 1239 in the AUC 4000 cohort and 4884 ± 766 for the AUC 5000 cohort. No patient in either cohort developed hepatic sinusoidal obstructive syndrome or seizures attributable to Bu. Primary graft failure occurred in 4 patients and secondary graft failure occurred in 3, predominantly in the AUC 4000 cohort (6 of 7). Among the engrafted patients (n = 28), 16 achieved full donor chimerism and 9 patients attained stable mixed chimerism. Overall survival of patients at 6 years after transplantation was 59.5% for the AUC 4000 cohort and 85.4% for the AUC 5000 cohort, with primary graft failure in the first cohort being a major contributor to morbidity. Logistic regression analysis showed that the risk of graft failure increased significantly if cord blood hematopoietic progenitor cells were used or if total Bu exposure was below 4000 µMol*minute per day for 2 days. The difference in clinical outcomes between the 2 cohorts supports the conclusion that targeting a higher Bu AUC of 5000 µMol*minute per day for 2 days improves donor engraftment in infants with nonmalignant conditions undergoing RIC HPCT without increasing toxicity. Measuring i.v. Bu pharmokinetics using a test dose allows timely adjustment of single daily regimen doses and optimization of total Bu exposure, resulting in an effective and safe regimen for these infants.

Impact of immune modulation with in vivo T-cell depletion and myleoablative total body irradiation conditioning on outcomes after unrelated donor transplantation for childhood acute lymphoblastic leukemia.

To determine whether in vivo T-cell depletion, which lowers GVHD, abrogates the antileukemic benefits of myeloablative total body irradiation-based conditioning and unrelated donor transplantation, in the present study, we analyzed 715 children with acute lymphoblastic leukemia. Patients were grouped for analysis according to whether conditioning included antithymocyte globulin (ATG; n = 191) or alemtuzumab (n = 132) and no in vivo T-cell depletion (n = 392). The median follow-up time was 3.5 years for the ATG group and 5 years for the alemtuzumab and T cell-replete groups. Using Cox regression analysis, we compared transplantation outcomes between groups. Compared with no T-cell depletion, grade 2-4 acute and chronic GVHD rates were significantly lower after in vivo T-cell depletion with ATG (relative risk [RR] = 0.66; P = .005 and RR = 0.55; P < .0001, respectively) or alemtuzumab (RR = 0.09; P < .003 and RR = 0.21; P < .0001, respectively). Despite lower GVHD rates after in vivo T-cell depletion, nonrelapse mortality, relapse, overall survival, and leukemia-free survival (LFS) did not differ significantly among the treatment groups. The 3-year probabilities of LFS after ATG-containing, alemtuzumab-containing, and T cell-replete transplantations were 43%, 49%, and 46%, respectively. These data suggest that in vivo T-cell depletion lowers GVHD without compromising LFS among children with acute lymphoblastic leukemia who are undergoing unrelated donor transplantation with myeloablative total body irradiation-based regimens.

Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita.

We describe outcomes after allogeneic transplantation in 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009. The median age at transplantation was 13 years (range, 2 to 35). Approximately 50% of transplantations were from related donors. Bone marrow was the predominant source of stem cells (24 of 34). The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II to IV acute GVHD and the 3-year probability of chronic graft-versus-host disease were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation because of graft failure (n = 6) or other transplantation-related complications; 9 of these patients had undergone transplantation from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years after transplantation, and 4 of these were attributed to pulmonary failure. Transplantation regimen intensity and transplantations from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing nonradiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease.

Relationship of race/ethnicity and survival after single umbilical cord blood transplantation for adults and children with leukemia and myelodysplastic syndromes.

The relationship of race/ethnicity with outcomes of umbilical cord blood transplantation (UCBT) is not well known. We analyzed the association between race/ethnicity and outcomes of unrelated single UCBT for leukemia and myelodysplastic syndromes. Our retrospective cohort study consisted of 885 adults and children (612 whites, 145 blacks, and 128 Hispanics) who received unrelated single UCBT for leukemia and myelodysplastic syndromes between 1995 and 2006 and were reported to the Center for International Blood and Marrow Transplant Research. A 5-6/6 HLA-matched unit with a total nucleated cell count infused of ≥2.5 × 10(7)/kg was given to 40% white and 42% Hispanic, but only 21% black patients. Overall survival at 2 years was 44% for whites, 34% for blacks, and 46% for Hispanics (P = .008). In multivariate analysis adjusting for patient, disease, and treatment factors (including HLA match and cell dose), blacks had inferior overall survival (relative risk of death, 1.31; P = .02), whereas overall survival of Hispanics was similar (relative risk, 1.03; P = .81) to that of whites. For all patients, younger age, early-stage disease, use of units with higher cell dose, and performance status ≥80 were independent predictors of improved survival. Black patients and white patients infused with well-matched cords had comparable survival; similarly, black and white patients receiving units with adequate cell dose had similar survival. These results suggest that blacks have inferior survival to whites after single UCBT, but outcomes are improved when units with a higher cell dose are used.

Allogeneic hematopoetic stem cell transplantation in pediatric myelodysplastic syndromes: improved outcomes for de novo disease.

We report 23 consecutive pediatric patients with MDS who received allogeneic HSCT on IRB approved protocols between 1992 and 2009 at Children's Memorial Hospital (Chicago, IL). Nine patients had de novo MDS, whereas 14 patients had treatment-related MDS. All patients had a documented cytogenetic abnormality, and monosomy 7/7q- was seen in 12 patients (52%). Fourteen of 23 patients received a myeloablative conditioning regimen; RIC regimens were used for the remaining nine. Five patients relapsed post-transplant, including four patients who received RIC transplant and four patients with treatment-related MDS. For the entire group, estimated five-yr RFS and OS were 47% and 50%, respectively. Treatment-related MDS was associated with decreased RFS in comparison with de novo MDS (33% vs. 70%, p = 0.05). Five-year OS rates reached 80% for those with de novo MDS. RIC regimens were associated with decreased three-yr RFS in comparison with myeloablative regimens (22% vs. 68%, p = 0.02). There was no correlation of survival with blast count at diagnosis, IPSS score, cytogenetic abnormality, donor type, or HLA match. Larger series are needed to confirm prognostic factors so that higher-risk patients can be targeted with novel approaches.

Early elevation of C-reactive protein correlates with severe infection and nonrelapse mortality in children undergoing allogeneic stem cell transplantation.

C-reactive protein (CRP) is an acute phase reactant that is a reliable marker of systemic inflammation and has been associated with increased morbidity and mortality following hematopoietic stem cell transplantation (HSCT) in adults. In this study, we evaluated whether early elevations of CRP were associated with various complications and nonrelapse mortality following HSCT in pediatric patients. Seventy pediatric patients had CRP levels drawn at regular time points during the first week following their transplants. Patients were followed for 100 days following transplant, and transplant-related complications were documented. Patients who subsequently developed severe infections had higher median CRP values than those without severe infections (median 8.03 mg/dL versus 1.64 mg/dL, P = .0008) as did those who suffered nonrelapse mortality compared with those who did not (12.6 mg/dL versus 2.44 mg/dL, P = .02). These findings suggest that elevated CRP values may be useful as a marker of individual pediatric patients with a higher risk for treatment-related morbidity and mortality.

Reduced-intensity conditioning regimens for allogeneic transplantation in children with acute lymphoblastic leukemia.

Reduced-intensity conditioning regimens have been used extensively in adults with hematologic malignancies. To address whether this is a feasible approach for children with acute lymphoblastic leukemia, we evaluated transplant outcomes in 38 recipients transplanted from 1995-2005 for whom this was their first transplant. The median age at transplant was 12 years, and 47% had performance scores <90%. Disease status was first complete remission (CR) in 13%, > or =CR2 in 60% of patients, and 22% had active disease at transplantation. Matched related donors were available for a third of patients, about half of whom received bone marrow (BM) and the others, peripheral blood progenitor cells. Sixty percent of unrelated donor transplant recipients received peripheral blood progenitor cells. The day-100 probability of grade II-IV acute graft-versus-host disease was 37% and the 3-year probability of chronic graft-versus-host disease, 26%. At 3 years, the probability of treatment-related mortality was 40%, relapse 37%, and disease-free survival 30%. These data indicate long-term DFS can be achieved using reduced-intensity conditioning regimens in children with acute lymphoblastic leukemia. Given the relatively small cohort, these findings must be validated in a larger population.

A phase II prospective study of sequential myeloablative chemotherapy with hematopoietic stem cell rescue for the treatment of selected high risk and recurrent central nervous system tumors.

High risk/recurrent CNS tumors have a poor prognosis. We studied tandem high dose chemotherapy (HDC) with hematopoietic progenitor stem cell rescues (HPCR) as potentially curative therapy. Twenty-four patients (mean age 6.8 years) were enrolled, 19 underwent HDC/HPCR. Diagnoses were medulloblastoma (n = 9), germ cell tumor (n = 4), high grade astrocytoma (n = 2), supratentorial PNET (n = 1), pineoblastoma (n = 2), or papillary meningioma (n = 1). Cytoreduction regimen #1 consisted of carboplatin (500 mg/m(2)) x 3 days, etoposide (250 mg/m(2)) x 3 days, and thiotepa (300 mg/m(2)) x 3 days. Patients without progression or excessive toxicity (n = 11), received regimen #2 with melphalan (60 mg/m(2)) x 3 days and cyclophosphamide (1,500 mg/m(2)) x 4 days. Projected overall/event-free survival for the 19 patients was 51/37% and 34/28% at 1 and 5 years, respectively. Toxicity was significant with six treatment related deaths including four with veno-occlusive disease. This regimen of sequential HDC/HPCR in high risk/recurrent CNS tumor patients is not feasible due to toxicity.

High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukaemia predicts poor event-free survival.

WT1 gene expression has been proposed as a useful marker of minimal residual disease in leukaemia. Its utility in paediatric haematopoietic stem cell transplantation (HSCT) has not been studied. We studied the prognostic value of WT1 expression in peripheral blood prior to HSCT in 36 children with acute myeloid leukaemia (AML). Samples were obtained 2 weeks pre-transplant to determine the level of WT1 expression. WT1 expression was normalized using K562 cells as a control and a relative value of 0.5 was chosen as the cut-off point between high and low WT1 expression. The median level of pre-transplant WT1 expression in the 36 patients was 0.09 (range 0.0001-11.0), with 11 patients having WT1 >or= 0.5 and 25, WT1 < 0.5. After HSCT, 76% of patients with high pre-transplant WT1 expression relapsed, in contrast to 0% of the patients with low WT1 expression. Those with high WT1 expression had significantly lower 5-year event-free survival (EFS) (18%, 95% CI 0-40%) as compared to those with low WT1 expression (68%, 95% CI 50-86%, P = 0.007). Multivariate analysis showed that pre-transplant WT1 level is the only significant prognostic factor for the difference in EFS. Our finding suggests that elevated WT1 gene expression before HSCT in paediatric AML predicts relapse and poor long-term EFS. A larger prospective study is warranted to compare the value of high WT1 expression and other markers of minimal residue disease in predicting clinical outcomes after HSCT.

Mycoplasma pneumoniae and atypical Stevens-Johnson syndrome in a hematopoietic stem cell transplant recipient.

Stevens-Johnson syndrome (SJS) is not typically reported following hematopoietic stem cell transplant (HSCT). The most severe form of SJS, which is toxic epidermal necrolysis (TEN) has been reported following HSCT, albeit very rarely. We describe a case of Mycoplasma-associated SJS following HSCT. While this association is commonly reported in previously healthy children, it has not been reported in patients following HSCT.

Dose intensive melphalan and cyclophosphamide with autologous hematopoietic stem cells for recurrent medulloblastoma or germinoma.

PURPOSE: To determine the response, toxicity, and survival for children with progressive or recurrent medulloblastoma and germinoma using a single myeloablative course of chemotherapy supported by autologous hematopoietic stem cells. PATIENTS AND METHODS: Subjects were in second remission or had minimal residual disease at the time of study entry. The conditioning regimen consisted of cyclophosphamide 6,000 mg/m(2) plus melphalan 180 mg/m(2). RESULTS: Twenty-nine evaluable pediatric patients were accrued. The most frequent major toxicities were myelosuppression, infections, and stomatitis, but no toxic deaths were recorded. Best responses were: CR = 6, CCR = 13, PR = 6, SD = 2, and PD = 2. There were 6 medulloblastoma and 3 germinoma survivors with a median follow-up of 7.5 years (range = 2.8-10). Two germinoma survivors received radiotherapy after autografting for presumptive progressive disease. CONCLUSION: Myeloablative chemotherapy consisting of cyclophosphamide and melphalan was tolerable in the relapsed brain tumor setting with 19/29 cases achieving CR or CCR status and 9/29 becoming long-term survivors.

Fecal calprotectin and serum albumin as markers of gastrointestinal graft versus host disease.

BACKGROUND: Acute graft versus host disease (aGVHD) affects approximately 30-60% of patients after allogeneic hematopoietic stem cell transplantation (HCT) and our ability to predict who develops this complication and their response to treatment is limited. Fecal calprotectin has recently gained popularity as an effective marker of GI inflammation in patients with Inflammatory Bowel Disease (IBD). METHODS: Fecal calprotectin and albumin were evaluated as prognostic and predictive markers of aGVHD in 60 adult and pediatric HCT patients. Stool samples were sent for calprotectin quantification prior to starting conditioning, at day 14 post-HCT, at day 28 post-HCT, and at onset of aGVHD ±â€¯2 days. RESULTS: Fecal calprotectin did not differentiate patients with GI-GVHD and non-GI GVHD and did not vary based on severity. However, in patients with steroid-refractory GI aGVHD, significantly higher fecal calprotectin levels were noted. At onset of lower-GI symptoms, steroid refractory patients (n = 3) had a mean fecal calprotectin level of 449 ug/g (range 116-1111 ug/g) and a mean albumin of 1.93 g/dL (range 1.6-2.3 g/dL) compared with a mean fecal calprotectin of 24 ug/g (range 16-31 ug/g) and a mean albumin of 3.3 g/dL (range 2.3-3.9 g/dL) in steroid responsive patients (n = 9) (fecal calprotectin p = 0.032, albumin p = 0.027). CONCLUSION: Patients with steroid-refractory GI aGVHD had higher fecal calprotectin levels and lower albumin levels than patients with steroid-responsive disease. We recommend further studies to evaluate non-invasive tests with fecal calprotectin in combination with albumin in predicting steroid refractory disease at onset of symptoms to potentially identify patients that may benefit from upfront escalation in GVHD treatment.

Treatment of relapsed Wilms' tumor with high-dose therapy and autologous hematopoietic stem-cell rescue: the experience at Children's Memorial Hospital.

PURPOSE: To investigate whether high-dose therapy with hematopoietic stem-cell rescue (HSCR) will improve survival for patients with relapsed Wilms' tumor. PATIENTS AND METHODS: Thirteen children with relapsed Wilms' tumor were treated with one or two cycles of high-dose chemotherapy (HDT) followed by autologous HSCR. Twelve of 13 patients received reinduction chemotherapy before HDT and HSCR. The median age at diagnosis was 4.8 years, and the median time to relapse was 12 months. The histology was favorable in 12 of 13 patients. The ablative regimens included: (1) thiotepa (TT)/cyclophosphamide (CTX)/carboplatin (CP; n = 2); (2) TT/CTX (n = 5); (3) TT/etoposide (ETP; n = 1); and (4) CP/ETP/CTX (n = 1). Four patients received two cycles of HDT and HSCR. Cycle 1 consisted of CP/ETP/CTX, and melphalan/CTX were used in cycle 2. RESULTS: Seven of 13 patients are alive without evidence of disease, with a median follow-up of 30 months. The 4-year estimated event-free survival (EFS) rate is 60% (95% CI, 0.40 to 6.88), and the overall survival (OS) at 4 years is 73% (95% CI, 0.40 to 6.86). There was no transplant-related mortality. All patients engrafted to an absolute neutrophil count 500/microL at a median of 13 days (range, 8 to 62 days) and had an unsustained platelet count > 20.0 micro at a median of 16 days (range, 10 to 202 days). CONCLUSION: Our results suggest that HDT with HSCR is an effective treatment for patients with Wilms' tumor who experience relapse.