Adams, Roberta

OBJECTIVES: The last decade has seen improved outcomes for children requiring extracorporeal life support as well as for children undergoing hematopoietic cell transplantation. Thus, given the historically poor survival of hematopoietic cell transplantation patients using extracorporeal life support, the Pediatric Acute Lung Injury and Sepsis Investigators’ hematopoietic cell transplantation and cancer immunotherapy subgroup aimed to characterize the utility of extracorporeal life support in facilitating recovery from critical cardiorespiratory illnesses in pediatric hematopoietic cell transplantation patients. DATA SOURCES: All available published data were identified using a set of PubMed search terms for pediatric extracorporeal life support and hematopoietic cell transplantation. STUDY SELECTION: All articles that provided original reports of pediatric hematopoietic cell transplantation patients who underwent extracorporeal life support were included. Sixty-four manuscripts met search criteria. Twenty-four were included as primary reports of pediatric hematopoietic cell transplantation patients who underwent extracorporeal life support (11 were single case reports, four single institution case series, two multi-institution case series, and seven registry reports from Extracorporeal Life Support Organization, Pediatric Heath Information System, and Virtual Pediatric Systems). DATA EXTRACTION: All 24 articles were reviewed by first and last authors and a spread sheet was constructed including sample size, potential biases, and conclusions. DATA SYNTHESIS: Discussions regarding incorporation of available evidence into our clinical practice were held at biannual meetings, as well as through email and virtual meetings. An expert consensus was determined through these discussions and confirmed through a modified Delphi process. CONCLUSIONS: Extracorporeal life support in hematopoietic cell transplantation patients is being used with increasing frequency and potentially improving survival. The Pediatric Acute Lung Injury and Sepsis Investigators hematopoietic cell transplantation-cancer immunotherapy subgroup has developed a framework to guide physicians in decision-making surrounding extracorporeal life support candidacy in pediatric hematopoietic cell transplantation patients. In addition to standard extracorporeal life support considerations, candidacy in the hematopoietic cell transplantation population should consider the following six factors in order of consensus agreement: 1) patient comorbidities; 2) underlying disease necessitating hematopoietic cell transplantation; 3) hematopoietic cell transplantation toxicities, 4) family and patient desires for goals of care; 5) hematopoietic cell transplantation preparatory regimen; and 6) graft characteristics. Although risk assessment may be individualized, data are currently insufficient to clearly delineate ideal candidacy. Therefore, we urge the onco-critical care community to collaborate and capture data to provide better evidence to guide physicians’ decision-making in the future.

Abstract The Wilms tumor protein,WT1, is a potentially targetable tumor associated antigen that is overexpressed in a majority of pediatric leukemias. T cells with cytotoxic activity restricted to WT1 peptide can be expanded from the peripheral blood of normal donors using pulsed EBV transformed BLCLs as stimulators. As part of an ongoing clinical trial, a patient with multiply relapsed leukemia cutis was successfully treated with donor derived WT1 CTLs. The patient was initially diagnosed with MLL rearranged AML at 3 months of age with marrow and cutaneous involvement. By 3.5 years of age, he had undergone two stem cell transplants (SCT) from a sex-mismatched HLA matched unrelated donor. Multiple episodes of isolated cutaneous relapse starting two months after the second SCT were treated with DLI at escalating doses (3.3 x 10e8/kg) as well as local radiotherapy with continued development of new lesions. He was started on Interferon 2b alpha five months after second SCT with good response but was taken off of it for clinical intolerance and one month later again developed cutaneous lesions for which he received DLI, radiotherapy and was restarted on low dose Interferon 2b alpha with stabilization of disease. Biopsy of one of the lesions demonstrated the presence of MLL rearranged leukemic blasts that by PCR demonstrated WT1 expression. WT1 directed CTLs were generated from his SCT donor. These WT1 CTLs were restricted by HLA-DRB1 0801. The immunodominant epitopes presented by this allele were defined (281- 292 and 425-436) using overlapping pools of pentadecapeptides. The CTLs were cytotoxic at 25:1 E:T ratio against autologous BLCLs (33%) and autologous BLCLs loaded with the WT1 peptides (65%) but not against HLA mismatched BLCLs (2%) or K562 cells (0%). The line was composed of a mix of CD8 (64%) and CD4 (30%) T cells. The patient was treated on Day 0,7, 21 and 35 with 30 x 10e6/m2 of WT1 CTLs. The first cycle of therapy was associated with resolution of one of the skin lesions and he went on to receive two additional cycles of WT1 CTLs. Expansion of circulating WT1 and EBV specific precursors in the blood was detected after these infusions. One of two residual skin lesions was biopsied and demonstrated no active leukemic infiltrate and the presence of donor derived T cells. However, at no time prior to or following the WT-1 specific T-cell infusions has he developed any cutaneous or other evidence of GvHD. Based on uncertainty about the duration of WT1 CTL maintenance in vivo the patient has received multiple cycles of T cell infusions. Strikingly, each cycle of cells has resulted in an expansion of circulating WT1 and EBV specific precursors. The patient is now 5 years old and has been in continuous remission for 20 months. Prior studies have focused almost exclusively on vaccines and T-cell therapies specific for immunogenic epitopes of WT-1 presented by prevalent class I HLA alleles. This patient provides evidence underscoring the therapeutic potential of T-cells specific for immunogenic WT-1 peptides presented by HLA class II alleles. Disclosures: No relevant conflicts of interest to declare.