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Supplemental Table 1

Purpose:In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.Patients and Methods:We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.Results:Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS.Conclusions:This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

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The utility of transbronchial biopsy in the management of pulmonary complications following hematopoietic stem cell transplantation has shown variable results. Herein, we examine the largest case series of patients undergoing transbronchial biopsy following hematopoietic stem cell transplantation. We performed a retrospective analysis of 130 transbronchial biopsy cases performed in patients with pulmonary complications post-hematopoietic stem cell transplantation. Logistic regression models were applied to examine diagnostic yield, odds of therapy change and complications. The most common histologic finding on transbronchial biopsy was a non-specific interstitial pneumonitis (n= 24 cases, 18%). Pathogens identified by transbronchial biopsy were rare, occurring in < 5% of cases. A positive transbronchial biopsy significantly increased the odds of a subsequent change in corticosteroid therapy (OR=3.12, 95% CI 1.18–8.23; p=0.02) but was not associated with a change in antibiotic therapy (OR=1.01, 95% CI 0.40–2.54; p=0.98) or changes in overall therapy (OR=1.92, 95% CI 0.79–4.70; p=0.15). Patients who underwent a transbronchial biopsy had increased odds of complications related to the bronchoscopy (OR=3.33, 95% CI 1.63–6.79; p=0.001). In conclusion, transbronchial biopsy may contribute to the diagnostic management of non-infectious lung injury post-hematopoietic stem cell transplantation, while its utility in the management of infectious pulmonary complications of HSCT remains low.

Allogeneic hematopoietic cell transplantation (HCT) has been increasingly used in the setting of FMS-like tyrosine kinase-3 (FLT3)-mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD (internal tandem duplication) mutational testing. FLT3-mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs 37%, P

A severe umbilical cord stem cell infusion reaction due to dextran in an atopic pediatric patient

Contains fulltext : 182594.pdf (Publisher’s version ) (Closed access) The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that use myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting. We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2 to 4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day -10 and continued through day +100 post-HCT. Median age was 56 years (range, 18-69 years), and 95% had acute myelogenous leukemia or high-risk myelodysplastic syndrome. Vorinostat was safe and tolerable. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 22%, and for grade 3 to 4 it was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, nonrelapse mortality, GVHD-free relapse-free survival, and overall survival at 1 year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in peripheral blood mononuclear cells and reduced interleukin 6 (P = .028) and GVHD biomarkers (Reg3, P = .041; ST2, P = .002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT01790568.

Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with (131)I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after (131)I-MIBG have not been defined. This is a multi-institutional retrospective review of patients with neuroblastoma treated with (131)I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to (131)I-MIBG. A competing riskregression was used to identify potential risk factors for SMN. The analytical cohort included 644 patients treated with (131)I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4-13.0%) and 14.3% (95% CI, 8.3-23.9%) at 5 and 10 years from first (131)I-MIBG, respectively. No increase in SMN risk was found with increased number of (131)I-MIBG treatments or higher cumulative activity per kilogram of (131)I-MIBG received (p=0.72 and p=0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p&nbsp

Analytic morphomics is a novel methodology that uses high-throughput computed tomography (CT) processing techniques to generate reproducible body measurements (Supplementary Table).1, 2, 3, 4 Body mass index is widely used in clinical and public health studies to predict mortality risk.5 Indeed, we recently examined its impact in allogeneic hematopoietic cell transplantation (HCT) and found that obese patients were at significantly greater risk of mortality compared with normal weight individuals.6 Unfortunately, body mass index does not reliably distinguish adipose tissue mass from muscle mass.7 Therefore, we sought to index patient size using CT measurements.2 The aim of the current study was to apply analytic morphomics in a cohort of allogeneic HCT patients and correlate with clinical outcomes.

Hepatic dysfunction following hematopoietic stem cell transplantation (HSCT) is common, but making the correct diagnosis can be challenging. Liver biopsies can serve as an important diagnostic tool when the etiology cannot be clearly determined by laboratory data, physical examination, and imaging studies. We reviewed 12 consecutive pediatric patients (seven males, five females, age 9-23 years) who received allogeneic HSCT and underwent a laparoscopic-guided liver biopsy for hepatic dysfunction of unknown etiology from 1998 to 2005. Biopsies were performed using a single-port technique with a 16 or 18 gauge, spring-loaded biopsy gun. The time from HSCT to biopsy ranged from 31 days to 821 days (median 92 days). No intra- or postoperative complications were observed. The initial clinical diagnosis was confirmed in seven patients, whereas the initial working diagnosis was inaccurate in the remaining five patients. Our results suggest that laparoscopic-guided liver biopsy is an informative and safe procedure in pediatric HSCT recipients; this approach helped delineate the true cause of hepatic dysfunction and changed our therapeutic approach in approximately 40% of the patients reviewed. While the safety record at our institution appears promising, a larger multi-institutional study would be necessary to more accurately describe the overall efficacy of this procedure in pediatric HSCT patients.

Allogeneic hematopoietic stem cell transplantation (SCT) is an important therapeutic option for a number of malignant and nonmalignant conditions but the broader application of this treatment strategy is limited by several side effects. In particular, diffuse lung injury is a major complication of SCT that responds poorly to standard therapeutic approaches and significantly contributes to transplant-related morbidity and mortality. Historically, approximately 50% of all pneumonias seen after SCT have been secondary to infection, but the judicious use of broad-spectrum antimicrobial prophylaxis in recent years has tipped the balance of pulmonary complications from infectious to noninfectious causes. This mini review will discuss the definition, risk factors and pathogeneses of noninfectious lung injury that occurs early after allogeneic SCT.

Currently, limited data exist on the role of tacrolimus (FK506) in pediatric allogeneic marrow transplantation. Forty-one patients who received tacrolimus as prophylaxis were reviewed, with a median age of 9 years (range 0.2-16 years). Twenty-one patients underwent related donor transplants and 20 underwent unrelated donor transplants. All patients received tacrolimus beginning the day prior to transplant at a dose of 0.03 mg/kg/day by continuous i.v. infusion. When clinically possible, patients were switched to oral therapy in two divided doses, at four times the intravenous dose. Tacrolimus levels were monitored twice a week, and dosages adjusted to maintain serum levels 5-15 ng/ml. Common adverse effects included hypomagnesemia (98%), hypertension (49%), nephrotoxicity (34%), and tremors (32%). Less common side-effects (10% cases) included seizures and hyperglycemia. The median time to ANC recovery (ANC500 x 106/l) was 15 days. For the related donor group, the incidence of grade II-IV acute GVHD was 33%, and grade III-IV GVHD 19%. For the unrelated donor group, the incidence of grade II-IV acute GVHD was 55%, and grade III-IV GVHD 30%. Overall, tacrolimus therapy was well tolerated as prophylaxis for acute GVHD in pediatric patients undergoing allogeneic transplantation.

Between October 1995 and October 1998, 24 children aged 9 months to 17 years (median 11 years) underwent cytokine-mobilized allogeneic peripheral blood stem cell (PBSC) transplantation for treatment of hematological disorders. All of the transplants were the first allogeneic transplant for the recipient. Twenty patients were transplanted for hematological malignancies (ALL = 8, AML = 6, CML = 4, MDS = 2) and four patients were transplanted for non-malignant disease (thalassemia major = 2, Wiskott-Aldrich syndrome = 1, Kostmann's syndrome = 1). Nineteen donors were HLA-identical siblings, four were HLA-matched or single antigen mismatched parents, and one was a syngeneic transplant. Donors aged 8 to 38 years (median 15 years, 14 donors18 years) received G-CSF 10 microg/kg/day subcutaneously beginning 4 days before PBSC collection and were submitted to one to three leukapheresis collections. The median CD34+ cell yield was 7.8 x 106 cells/kg recipient body weight. All patients achieved an ANC0.5 x 109/l after a median of 13 days (range 10-21). Twenty-three patients eventually achieved platelet transfusion independence. One patient died on day 63 without ever achieving platelet transfusion independence. Four patients received platelet transfusions to maintain a platelet count well above 20 x 109/l due to bleeding complications. Of the 19 evaluable patients, the median time to a non-transfused platelet count of 20 x 109/l was 12 days (range 0-44). Ten of 23 at-risk patients developed acute GVHD grades II to IV, with grades III to IV in four patients. Twelve of 19 patients followed for at least 100 days have developed chronic GVHD (extensive = 2, limited = 10) with an actuarial risk of chronic GVHD of 75% at 1 year. The Kaplan-Meier estimate of event-free survival is 65% at 2 years. Four patients died (GVHD = 3, VOD = 1), three patients relapsed, and one patient with thalassemia major had a late graft failure with autologous recovery. Based upon our experience, allogeneic PBSCT is safe for both pediatric donors and recipients and engraftment of neutrophils and platelets is rapid. Bone Marrow Transplantation (2000) 25, 13-18.

Purpose. 123I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N=82) and immunohistochemistry (IHC; N=61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6–73.7%) versus 5.9% (range 0.6–110.0%) for the 8 nonavid patients (P=0.31). Median percent NET protein expression was 50% (range 0–100%) in MIBG avid patients compared to 10% (range 0–80%) in nonavid patients (P=0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P=0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.

(131)I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical with activity in patients with relapsed or refractory neuroblastoma. Irinotecan is a known radiosensitizer with activity in neuroblastoma. This phase I study aimed to determine the recommended phase 2 dose of MIBG together with fixed doses of vincristine and irinotecan.Patients 1 to 30 years old with relapsed or refractory neuroblastoma and MIBG-avid tumors were eligible. All patients had autologous hematopoietic stem cells (PBSC) available and met standard phase I organ function requirements. Irinotecan (20 mg/m(2)/dose IV) was given on days 0 to 4 and 7 to 11, with vincristine (1.5 mg/m(2) IV) on days 0 and 7. MIBG was given on day 1 following a 3 + 3 phase I dose escalation design starting at 8 mCi/kg MIBG. PBSCs were administered at dose level 8 mCi/kg for prolonged myelosuppression and for all patients at 12 mCi/kg or more.Twenty-four patients evaluable for dose escalation (median age, 6.7 years; range, 1.9-26.8 years) received 1 (n = 17), 2 (n = 5), or 3 (n = 2) cycles of therapy. Myelosuppression and diarrhea were the most common toxicities. Two of 6 patients at the 18 mCi/kg dose level had dose-limiting toxicity (DLT), including one with protocol-defined DLT with prolonged mild aspartate aminotransferase elevation. Eighteen mCi/kg was the recommended phase 2 dose. Six additional patients were treated at 18 mCi/kg, with one additional DLT. Responses (2 complete and 4 partial responses) occurred in 6 of 24 (25%) evaluable patients.MIBG is tolerable and active at 18 mCi/kg with standard doses of vincristine and irinotecan.

CLL remains incurable with the standard therapy. Allogeneic hematopoietic stem cell transplant may be curative. We examined 50 patients with advanced CLL who underwent allogeneic HCT at the University of Michigan between 1996 and 2006. Twenty-one patients received reduced-intensity conditioning (RIC) and twenty-nine patients received full-intensity conditioning (FIC) consisting of CY, etoposide and BCNU (n=20) or BU and CY (n=9). RIC recipients were older than FIC recipients (median age 54 vs 51, P=0.009). There were no statistically significant differences between groups in terms of the number of earlier therapies or patients with adverse cytogenetics. There were more unrelated donors in the RIC group 62% than in the FIC group 31% (P=0.030). Despite their older age and greater use of URD, the 5-year overall survival (OS) rate was 63% in the RIC group as compared with 18% in the FIC group (P=0.006). The primary cause of inferior survival in the FIC recipients was TRM, which was twice as high at day 100 for the FIC group 27% compared with the RIC group 14% (P=0.005). The relapse rate was 15% regardless with the majority of relapses occurring after day 100. These results suggest a favorable outcome for advanced CLL who undergo a RIC regimen compared with FIC.

Severe congenital neutropenia (SCN) is a hematologic condition characterized by arrested maturation of myelopoiesis at the promyelocyte stage of development. With appropriate treatment using recombinant human granulocyte-colony-stimulating factor (r-HuG-CSF), SCN patients are now surviving longer, but are at increased risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but transplantation outcomes after malignant transformation are not well established. We report results for six patients with SCN who underwent HSCT for MDS or AML between 1997 and 2001 at two transplant centers. Two patients transplanted for MDS survived. Both of these patients were transplanted without being given induction chemotherapy. Four patients, who all received induction chemotherapy for AML prior to HSCT, died. Administering induction chemotherapy prior to HSCT resulted in significant morbidity. Rapid transplantation should be the goal for the SCN patient once the diagnosis of MDS/AML is established. SCN patients should be monitored carefully for progression to MDS in order to be treated with HSCT as soon as they have progressed and before developing AML. For SCN patients who progress to AML, HSCT should still be considered, even though the risks appear to be greater.

Chronic graft versus host disease (GVHD) is a significant cause of morbidity and mortality in matched unrelated donor hematopoietic stem cell transplantation. Incidence of acute GVHD is a major risk factor for chronic GVHD. Calcineurin inhibitors form the backbone of graft versus host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation. When comparing cyclosporine to tacrolimus for GVHD prophylaxis, we previously reported a trend toward superiority of cyclosporine as prophylaxis against acute GVHD. We now analyze their effect on the incidence and severity of chronic GVHD. In a multi-institutional trial, we prospectively collected the clinical data on 141 evaluable patients receiving either cyclosporine/methotrexate or tacrolimus/methotrexate based prophylactic regimens for 6/6 matched unrelated donor, transplant. Conditioning regimens were fully ablative; no T-cell depletion was permitted; cord blood donors were excluded. Patients were required to receive either cyclosporine or tacrolimus, but the choice was per investigator preference. The two arms were reasonably balanced: 60.1% of patients received cyclosporine and 39.9% of patients received tacrolimus. Rates for acute GVHD were 60.4% for cyclosporine and 73.8% for tacrolimus (p = 0.086). Rates for chronic GVHD were 44.2% for cyclosporine and 47.3% for tacrolimus (p = 0.7). In the 61 patients with chronic GVHD, extensive disease was present in 82.9% of cyclosporine group and 80.8% of the tacrolimus group (p = 1.0) Those graded as moderate or severe comprised 80% of the cyclosporine group and 56% of the tacrolimus group (p = 0.46) and those both extensive and moderate or severe were 71.4% and 52%, respectively (p = 0.12). In pediatric matched unrelated donor transplantation, the incidence and severity of chronic graft versus host disease in patients receiving either tacrolimus/methotrexate or cyclosporine/methotrexate based regimens for prophylaxis of GVHD are not significantly different.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option with curative potential that exploits graft versus myeloma effect (GVM). However, myeloablative allogeneic HSCT has been associated with high transplant-related mortality and its impact on risk of relapse has been questioned. The differences in conditioning regimens, GVHD prophylaxis and short follow up have limited our ability to assess the impact of GVM when comparing allogeneic and autologous HSCT. Method: We evaluated the long term outcomes of 74 consecutive patients under the age of 60 who underwent autologous (n=46) or related allogeneic HSCT (n=28) between 3/1994 and 12/2000 following a single myeloablative conditioning regimen of TBI (3 Gy daily on days -10 to -8), oral Busulfan 2.4 mg/kg per day (day -7 to -4) and Cyclophosphamide 60 mg/kg IV daily (day-3 and -2). GVHD prophylaxis was tacrolimus or cyclosporine with or without methotrexate. Results: There were no significant differences observed between groups in regard to gender, immunoglobulin subtype, stage, and time to HSCT and disease status at HSCT. However, there were younger patients with advanced disease in the allogeneic group (Table 1). With median follow up of 10 years as of 12/2006, the allogeneic group had superior progression free survival than autologous group (37% v 9%; P = 0.04). After HSCT, 12 of 22 and 9 of 39 evaluable patients improved to complete remission in the allogeneic and autologous group, respectively (55% v 23%; P=0.02). Overall survival favored the allogeneic group but was not statistically significant (46% v 23%; P=0.56). The cumulative incidence of relapse was 18% in the allogeneic group and 74% in the autologous group (P=0.0001). The cumulative incidence of non-relapse mortality (NRM) was 32% in allogeneic group and 11% in autologous group (P=0.001). The cumulative incidence of acute GVHD (grade II-IV) was 46% and the cumulative incidence of chronic GVHD was 73%. Conclusion: The superior long term progression free survival and lower relapse rate in the allogeneic group suggests strongly GVM effect. However, the NRM in the allogeneic group partially offset the overall survival benefit. The higher than expected OS rate for both allogeneic and autologous group may be related to a beneficial effect of myeloablative conditioning. Future strategies with reduced toxicity myeloablative conditioning regimens and improved GVHD prophylaxis may reduce NRM while harnessing GVM effect. Selected Characteristics Characteristics Autologous Allogeneic P HSCT; hematopoietic stem cell transplantation, CR; complete remission, PR; Partial remission Median age at HSCT; y (range) 53 (38–59) 47 (30–56) 0.01 Disease status at HSCT, n 0.12 CR 11 (24%) 2 (7%) PR 32 (70%) 22 (79%) Stable or progressive 3 (6%) 4 (14%) Disease Status after HSCT, n 0.79 CR 20 (44%) 14 (50%) PR 13 (28%) 8 (29%) Stable or progressive 6 (13%) 0 (0%) Non-evaluable 7 (15%) 6 (21%) Figure Figure

Tumor necrosis factor (TNF) plays a crucial role in the pathogenesis of graft-vs-host disease (GVHD), the major cause of treatment-related mortality (TRM) after allogeneic bone marrow transplantation (BMT). We tested the hypothesis that early rises in TNF (on day 7 following BMT) predict the development of significant GVHD and TRM. Ratios of soluble TNF receptor 1 (TNFR1) levels (day 7 level/pre-BMT level) was used as a surrogate marker for TNF in 440 myeloablative allogeneic BMT pts with a median age of 42y (range 0-65y). There were 269 (61%) related donors pts and 171 (39%) unrelated donors pts. 82 pts (19%) of this cohort were children 17y and younger of whom 38 were related donor pts (46%), 38 unrelated donor pts (46%) and 6 cord blood pts (8%). The median day of onset of GVHD 2-4 was 27d. For the entire cohort, the mean day 7 TNFR1 ratio correlated with severity of GVHD (p