Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia (AL) patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age: 16–57 years) with relapsed/refractory AL undergoing HSCT (matched related, matched unrelated, or one-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range 1200–2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy since TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post transplant non-relapse mortality (NRM) rate was only 3.9% (95% CI: 0.7–12.0) at day +100 and 8.1% (95% CI: 2.5–18.0) at one year. The cumulative incidence of grade II–IV acute GVHD was 43.1% (95% CI: 29.2–56.3) and for grade III–IV was 13.7% (95% CI: 6.9–27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall one-year survival was 55.5% (95% CI: 40.7–68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100 day and 1 year NRM rate and no increased risk of GVHD with higher doses of radiation.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1− and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

Summary:involving the developing central nervous system, endocrine system and skeletal system, can be avoided. Busulfan pharmacokinetics have been studied since We analyzed plasma pharmacokinetics of busulfan in 64 children and young adults (age 2.8-26; median 11Ehrsson and Hassan 1 developed a gas chromatographic assay for plasma in 1983. In a preliminary study we have years) with homozygous ␤-thalassemia transplanted with bone marrow from HLA-identical sibling donors.shown previously that variations in plasma pharmacokinetics may be age-dependent, with children younger than 5 A uniform conditioning regimen was employed, using busulfan 14 or 16 mg/kg in 12 divided doses, and cycloyears having a shorter elimination half-life than adults. 2 Several other studies reported the relationship between high phosphamide 120 or 200 mg/kg. Three sets of parameters were examined in this homogenous patient popubusulfan plasma levels and drug-related toxicities, namely hepatic veno-occlusive disease (VOD) and seizures. 3,4 An lation: (1) factors that affect the plasma kinetics of busulfan, such as age and pre-transplant liver status inverse correlation was seen between steady-state busulfan plasma concentration and graft rejection in unrelated donor defined by liver function tests, ferritin levels and liver biopsy; (2) busulfan-related toxicity: occurrence of BMT in patients with multiple diagnosis. 5 However, all previous studies were conducted analyzing veno-occlusive disease, seizures and idiopathic interstitial pneumonitis; and (3) the relationship between heterogeneous patient populations. There has been no study in a large, uniform group of patients with a single disease, busulfan exposure and transplant outcome: engraftment delay or rejection, aplasia, occurrence of mixed without pre-transplant chemotherapy. We analyzed plasma pharmacokinetics of busulfan in 64 chimeras and mortality. Kinetic analysis of first and 10th dose (using area under the curve (AUC), maximum children and young adults with homozygous ␤-thalassemia transplanted with histocompatable sibling bone marrow. A and minimum concentration) as comparable, showing no sign of accumulation or decline in busulfan plasma uniform conditioning regimen was employed, using busulfan 14 or 16 mg/kg and CY 120 or 200 mg/kg. Busulfan levels over time. Age and liver status did not influence busulfan metabolism. No relationship was found clearance in relation to age and pre-transplant liver status was assessed and the relationship of busulfan exposure to between busulfan exposure and toxicities or transplant outcome. We conclude that busulfan monitoring is not engraftment, graft rejection and toxicities was studied. predictive in children and young adults with homozygous ␤-thalassemia receiving busulfan and high-dose cyclophosphamide along with histocompatable sibling Materials and methods donor marrow.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

To determine whether immune stimulation could reduce acute myelogenous leukemia (AML) lethality, dendritic cells (DCs) were pulsed with AML antigens and used as vaccines or generated in vivo by

Background Transplant-associated thrombotic microangiopathy (TMA) syndromes are reported to occur with increased frequency in transplant patients treated with siroliumus combined with a calcineurin inhibitor. We performed a retrospective study of all pediatric transplant patients at City of Hope who were administered combined tacrolimus/sirolimus (TAC/SIR) to determine the occurrence of TMA. Procedure This analysis includes forty-one consecutive patients between the ages of 2 and 20 (median age 9.1) who received an allogeneic hematopoietic stem cell transplant from any source and also received TAC/SIR for prevention or treatment of GVHD. Of those 41 patients, 20 received TAC/SIR as GVHD prohpylaxis and were designated the preventative group (PG), while 21 received TAC/SIR as treatment for GVHD and were designated the therapy group (TG). TMA occurrence in both groups was documented from day -1 of transplant to day 60 for the PG, and until 30 days after last dose for the TG. TMA was defined according to 2005 consensus criteria. Results Five of 20 patients in the PG, and 5 of 21 in the TG, experienced TMA, with an overall rate of 23.8% for the population. All ten patients with TMA showed elevated levels of TAC, SIR or both and nine of ten suffered from organ injury due to regimen-related toxicity or GVHD. Conclusion Physicians should exercise caution in the use of TAC/SIR in pediatric patients due to a high rate of TMA. It is not recommended for heavily pre-treated patients and peak levels of TAC/SIR must be very carefully controlled.

The controversy surrounding private banking of umbilical cord blood units (CBU), as a safeguard against future malignancy or other life-threatening conditions, raises many questions in pediatric clinical practice. Recent favorable experiences with autologous transplantation for severe aplastic anemia using privately stored CBU, suggested a possible utility. While private banking is difficult to justify statistically or empirically, there may exist rare cases where autologous transplant of stored umbilical CBU could be beneficial. The reality of privately banked CBU and the possibility for future discovery of additional indications for autologous cord blood transplant, motivated us to re-examine our attitudes towards private cord blood banking.

BackgroundBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematological malignancy with extremely poor outcome. The median overall survival for adult patients is 9–13 months. Pediatric patients are exceedingly rare with an unclear clinical course. Currently, no standardized therapy has been established, although an acute lymphoblastic leukemia type of treatment appears to be more effective in those patients who are able to tolerate aggressive chemotherapy. SL-401 is a targeted therapy directed to CD123, a protein ubiquitously expressed at high level on the surface of BPDCN blasts. In adult phase 2 trials, it has demonstrated efficacy with 90% overall response rate. No pediatric patients with BPDCN using SL-401 have been reported.Case presentationHere, we report the first pediatric experience of three children with BPDCN treated with SL-401 at our institution. All patients tolerated SL-401 without significant toxicities. One patient with multiply relapsed and refractory disease had no response. The other two cases had significant and rapid clinical improvement after the two courses of treatment. However, the response was transient, and growth of soft tissue mass was observed in-between cycles in both patients with large tumor burden.ConclusionsThis is the first report of SL-401 in pediatric patients with BPDCN. Sl-401 was well tolerated and can produce a promising response. Further testing this agent in children is warranted.