e2 45 Anghelescu DL, Burgoyne LL, Liu T, et al Clinical and diagnostic imag ing findings predict anesthetic complications in children presenting with malignant mediastinal masses Paediatr Anaesth 2007[.]
e2 45 Anghelescu DL, Burgoyne LL, Liu T, et al Clinical and diagnostic imaging findings predict anesthetic complications in children presenting with malignant mediastinal masses Paediatr Anaesth 2007;17:1090-1098 46 Ng A, Bennett J, Bromley P, et al Anaesthetic outcome and predictive risk factors in children with mediastinal tumours Pediatr Blood Cancer 2007;48:160-164 47 King DR, Patrick LE, Ginn-Pease ME, et al Pulmonary function is compromised in children with mediastinal lymphoma J Pediatr Surg 1997;32:294-300 48 Lee EY Evaluation of non-vascular mediastinal masses in infants and children: an evidence-based practical approach Pediatr Radiol 2009; 39(suppl 2):S184-S190 49 Hack HA, Wright NB, Wynn RF The anaesthetic management of children with anterior mediastinal masses Anaesthesia 2008;63: 837-846 50 Perger L, Lee EY, Shamberger RC Management of children and adolescents with a critical airway due to compression by an anterior mediastinal mass J Pediatr Surg 2008;43:1990-1997 51 Saraswatula A, McShane D, Tideswell D, et al Mediastinal masses masquerading as common respiratory conditions of childhood: a case series Eur J Pediatr 2009;168:1395-1399 52 Janka GE Hemophagocytic syndromes Blood Rev 2007;21:245-253 53 Castillo L, Carcillo J Secondary hemophagocytic lymphohistiocytosis and severe sepsis/systemic inflammatory response syndrome/ multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation Pediatr Crit Care Med 2009;10:387-392 54 Risma K, Jordan MB Hemophagocytic lymphohistiocytosis: updates and evolving concepts Curr Opin Pediatr 2012;24:9-15 55 Rosado FG, Kim AS Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis Am J Clin Pathol 2013;139:713-727 56 Gholam C, Grigoriadou S, Gilmour KC, et al Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management Clin Exp Immunol 2011;163:271-283 57 Bergsten E, Horne A, Aricó M, et al Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study Blood 2017;130(25): 2728-2738 58 Grenier MA, Lipshultz SE Epidemiology of anthracycline cardiotoxicity in children and adults Semin Oncol 1998;25:72-85 59 Adams MJ, Lipshultz SE Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention Pediatr Blood Cancer 2005;44:600-606 60 Lipshultz SE, Miller TL, Scully RE, et al Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes J Clin Oncol 2012;30:1042-1049 61 Getz KD, Sung L, Ky B, et al Occurrence of treatment-related cardiotoxicity and its impact on outcomes among children treated in the AAML0531 clinical trial: A report from the children’s oncology group J Clin Oncol 2019;37(1):12-21 62 Lipsultz SE, Sambatokos P, Maguire M, et al Cardiotoxicity and cardioprotection in childhood cancer Acta Haematol 2014;132:391 63 Wu MY, Liu PJ, Lin PJ, et al Resuscitation of acute anthracyclineinduced cardiogenic shock and refractory hypoxemia with mechanical circulatory supports: pitfalls and strategies Resuscitation 2009; 80:385-386 64 Hinchey J, Chaves C, Appignani B, et al A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996;334:494-500 65 Casey S, Sampaio R, Michel E, Truwit C Posterior reversible encephalopathy syndrome: utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions AJNR Am J Neuroradiol 2000;21:1199-1206 66 Kim SJ, Im SA, Lee JW, et al Predisposing factors of posterior reversible encephalopathy syndrome in acute childhood leukemia Pediatr Neurol 2012;47:436-442 67 Endo A, Fuchigami T, Hasegawa M, et al Posterior reversible encephalopathy syndrome in childhood: report of four cases and review of the literature Pediatr Emerg Care 2012;28(2):153-157 68 Maude SL, Laetsch TW, Buechner J, et al Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia N Engl J Med 2018;378(5):439-448 69 Gardner RA, Finney O, Annesley C, et al Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults Blood 2017;129(25):3322-3331 70 Neelapu SS, Locke FL, Bartlett NL, et al Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma N Engl J Med 2017;377(26):2531-2544 71 Lee DW, Santomasso BD, Locke FL, et al ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells Biol Blood Marrow Transplant 2019; 25(4):625-638 72 Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase dose-escalation trial Lancet 2015;385(9967):517-528 73 Xu XJ, Tang YM Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells Cancer Lett 2014;343:172-178 74 Teachey DT, Lacey SF, Shaw PA, et al Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia Cancer Discov 2015;6(6):664-679 75 Navarro G, Taroumian S, Barroso N, Duan L, Furst D Tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums Semin Arthritis Rheum 2014;43:458-469 76 Yokota S, Miyamae T, Imagawa T, et al Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis Arthritis Rheum 2005;52:818-825 77 Grupp SA, Kalos M, Barrett D, et al Chimeric antigen receptormodified T cells for acute lymphoid leukemia N Engl J Med 2013; 368:1509-1518 78 Gardner R, Ceppi F, Rivers J, et al Preemptive mitigation of CD19 CAR T cell cytokine release syndrome without attenuation of antileukemic efficacy Blood 2019 79 Gust J, Hay KA, Hanafi LA, et al Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells Cancer Discov 2017; 7(12):1-16 e3 Abstract: Anemia and thrombocytopenia commonly occur in the pediatric intensive care unit (ICU) Hyperleukocytosis, superior vena cava (SVC) syndrome, spinal cord compression, and acute airway compromise in anterior mediastinal masses are oncologic emergencies that require a multidisciplinary approach to treat the invasive tumor and optimize outcomes New therapies, such as chimeric antigen receptor T cells, have brought new oncologic emergencies to the ICU As treatments for pediatric oncologic conditions improve, the pediatric intensivist must continue to understand “classic” hematologic and oncologic emergencies but also be ready to manage new emergencies that arise from these new treatments Key words: anemia, oncology, tumor lysis, bleeding, PRES, cytokine release syndrome 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation PRAKADESHWARI RAJAPREYAR, JENNIFER MCARTHUR, CHRISTINE DUNCAN, RACHEL PHELAN, ROBERT T TAMBURRO JR PEARLS • • • Outcomes for allogeneic hematopoietic cell transplant (HCT) patients requiring intensive care unit care have improved over the past decades Both acute and late cardiac complications occur in HCT Etiologies for this cardiac dysfunction include previous cardiotoxic treatments and therapies such as anthracyclines, cyclophosphamide, irradiation, iron overload, hyperhydration therapies, blood product transfusions, impaired renal function, sepsis, acute graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy, and genetic susceptibility HCT patients experiencing respiratory symptoms, including a new oxygen requirement, deserve prompt evaluation by the critical care team, as they are at risk for rapid development of respiratory failure Hematopoietic progenitor cell transplantation has evolved as treatment for a variety of congenital and acquired malignant and nonmalignant disorders Over the years, the name of this procedure has changed with attempts to be more accurate Throughout the literature, it has been referred to as bone marrow transplant (BMT), hematopoietic progenitor cell transplant (HPCT), or hematopoietic stem cell transplant (HSCT) Most recently, it is referred to as hematopoietic cell transplant (HCT) The first successful pediatric BMT occurred in a child with combined immunodeficiency Reported in 1968, the patient received marrow from a human leukocyte antigen (HLA)-matched sibling.1 Presently, in adults and children, the majority of allogeneic transplants are performed for the treatment of malignant disorders such as leukemias and lymphomas, although the field continues to expand to include nonmalignant disorders such as autoimmune disorders, metabolic diseases, immunodeficiencies, and hemoglobinopathies Since its inception, the field of pediatric HCT has demonstrated vast improvements in morbidity and • • • Patients undergoing allogeneic HCT experience prolonged immune dysregulation and are at risk for both opportunistic infection and GVHD Patients who develop GVHD are at high risk for developing other transplant-related toxicities Neurologic complications contribute significantly to the morbidity and mortality following HCT Seizures are the most common neurologic complication; encephalopathy, motor function deficits, cranial nerve palsies, visual disturbances, and impaired coordination may also occur Leukoencephalopathy primarily occurs in HCT patients who receive cranial radiation and/or intrathecal chemotherapy Peripheral nervous system neurotoxicity also occurs posttransplantation as an immune-mediated complication mortality related to transplantation; however, there are still many hurdles to overcome The major contributors to morbidity and mortality of allogeneic transplantation continue to be relapse of disease, transplant-related toxicity, infection, and graft-versushost disease (GVHD) Sources of Hematopoietic Progenitor Cells and Identification of Donors HCT involves transplanting hematopoietic progenitor cells from a donor source into a recipient These stem cells are capable of self-renewal and terminal differentiation that ultimately give rise to myeloid cells, lymphocytes, erythrocytes, and platelets (Fig 93.1) The donor source of these stem cells can be from the patient/recipient (autologous) or from another individual (allogeneic) The source of the donor (autologous vs allogeneic) is dependent on the indication for which the transplant is 1113 1114 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology T lymphocyte Common lymphoid progenitor B lymphocyte NK cells LT-HSC ST-HSC Megakaryocyte MEP Erythrocyte Common myeloid progenitor Granulocyte GMP Monocyte • Fig 93.1 As hematopoietic stem cells divide, they give rise to common lymphoid and common myeloid precursor cells that eventually generate all mature blood lineages of the body GMP, Granulocyte-monocyte precursors; LT-HSC, long-term hematopoietic stem cells; MEP, megakaryocyte-erythrocyte precursors; NK, natural killer; ST-HSC, short-term hematopoietic stem cells (Modified from Leung AYH, Verfaillie CM Stem cell model of hematopoiesis In: Silberstein LE, Anastasi J, Hoffman R, et al, eds Hematology: Basic Principles and Practice 4th ed Philadelphia: Elsevier; 2001.) being performed Traditionally, HCT has been performed using stem cells obtained from bone marrow However, stem cells can be mobilized into the peripheral blood and harvested for transplant These peripheral blood stem cells (PBSCs) allow for faster hematopoietic recovery and possibly less tumor contamination than bone marrow when used in autologous transplantation However, there may be more side effects in the allogeneic setting, particularly increased incidence of GVHD.2 Umbilical cord blood has also been shown to contain large numbers of stem cells capable of reconstituting hematopoiesis The first HCT using cord blood was performed in 1988 for a child with Fanconi anemia.3 Since then, unrelated cord blood stem cells have been used and numerous public cord blood banks have been established worldwide In circumstances in which there is no matched unrelated donor or cord blood found in a timely fashion, haploidentical transplantation can be performed using a parent or a sibling as donor Histoincompatibility barriers of a mismatched transplantation are overcome by using mega-doses of stem cells However, for this to be successful, a majority of the T cells have to be removed from the graft to prevent severe GVHD Unfortunately, this increases the risk for severe infection and relapse of the patient’s original disease.4,5 More recently, centers have been using several in vivo and ex vivo graft manipulation techniques to abrogate these risks.6–8 HLAs are expressed on the surface of various cells, in particular white blood cells (WBCs) These antigens are also known as the major histocompatibility complex, with relevant genes on the short arm of chromosome 6.9 This genetic region has been divided into chromosomal regions, called classes Classes I and II are important in transplantation Class I is made up of HLA-A, HLA-B, and HLA-C Class II is made up of HLA-DR, HLA-DP, and HLA-DQ, as well as variations on these genes Traditionally, the loci critical for matching for a bone marrow donor are HLA-A, HLA-B, and HLA-DR HLA-C and HLA-DQ have recently gained importance and are now considered in determining the best available donor.9,10 Ideally, a matched sibling donor is the best donor for a patient However, only 25% of patients with siblings are fortunate to have a matched sibling donor If there is no sibling donor, an alternative donor is identified using the National Marrow Donor Program (NMDP), which has approximately 12.5 million potential donors and nearly 209,000 cord blood units available for patients who need an HCT.11 As the degree of mismatch between patient and donor increases, so the risks of complications from transplantation, especially GVHD and graft failure Indications and Outcomes HCT has been used for a variety of diseases Autologous transplantation has traditionally been used to treat nonhematologic malignant diseases by escalating the doses of chemotherapy to myeloablative doses in hopes of eradicating the cancer Recently, CHAPTER 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation successive (two or three) autologous transplants have been performed, particularly in brain tumors and neuroblastoma The rationale of giving hematopoietic stem cells after the chemotherapy is completed is to minimize the period of neutropenia; it is hoped that this will reduce the number of infections and life-threatening complications.2 Allogeneic HCT is performed for hematologic cancers In children, these are most commonly acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) It is also used to treat hematologic diseases, including sickle cell anemia, thalassemias, and severe aplastic anemia A variety of immunodeficiencies and metabolic disorders are cured by allogeneic transplant, including severe combined immunodeficiency and hemophagocytic lymphohistiocytosis (Box 93.1).2 Survival from HCT has improved in recent years In autologous transplantation, the incidence of treatment-related mortality is less than 10% However, the majority of treatment failures are due to recurrent disease The event-free survival rate (EFS) for autologous HCT for high-risk neuroblastoma previously ranged from 33% to 66%, but a recent trial using tandem myeloablative autologous transplants demonstrated an improvement to 73.7% EFS.12–17 For recurrent or refractory non-Hodgkin lymphoma, the EFS in autologous HCT ranges from 27% to 59% In relapsed or refractory Hodgkin disease, the EFS ranges from 20% to 62%.18,19 • BOX 93.1 Current Indications for Pediatric Hematopoietic Progenitor Cell Transplantation Autologous Transplantation Malignant disorders • High-risk neuroblastoma • Relapsed non-Hodgkin lymphoma • Relapsed Hodgkin disease • Medulloblastoma • Germ cell tumors • Brain tumors • Relapsed Ewing sarcoma Nonmalignant disorders Autoimmune disorders Allogeneic Transplantation Malignant disorders • Acute myelogenous leukemia • Acute lymphoblastic leukemia • Chronic myeloid leukemia • Myelodysplastic syndromes • Juvenile myelomonocytic leukemia Nonmalignant disorders • Aplastic anemia • Fanconi anemia • Severe combined immunodeficiency • Thalassemia major • Diamond-Blackfan anemia • Sickle cell anemia • Wiskott-Aldrich syndrome • Osteopetrosis • Inborn errors of metabolism • Hemophagocytic lymphohistiocytosis • Shwachman-Diamond syndrome • Congenital immune deficiencies 1115 Among children with ALL, allogeneic transplantation is generally reserved for patients with high-risk disease, including patients who fail to achieve remission or who relapse after chemotherapy Among the 1494 patients younger than 18 years receiving an HLA-matched sibling transplant for ALL between 2006 to 2016, the 3-year survival rates range from 45% to 74% depending on their disease status going into transplantation The corresponding survival rates among the 2827 recipients of an unrelated donor transplant range from 47% to 68%.20 For pediatric patients with AML transplanted with matched sibling donors between 2006 and 2016, the 3-year survival rates following transplant range from 30% to 70%.20 Allogeneic HCT is the treatment of choice for young patients with severe aplastic anemia and an available HLA-matched sibling donor These patients have had excellent outcomes in recent years, with survival rates ranging from 79% for unrelated donor transplants to 92% for matched sibling transplants.20 Transplant outcomes for other nonmalignant diseases have also improved, with Fanconi anemia patients having a 5-year overall survival of 60% to 94%,21–24 Wiskott-Aldrich disease at 90%, and severe combined immunodeficiency at 71% to 94%.25,26 For inherited metabolic disorders, the overall survival of pediatric patients with adrenoleukodystrophy/metachromatic leukodystrophy is approximately 60% to 89% depending on the degree of neurologic dysfunction prior to HCT For Hurler syndrome, the overall survival is approximately 95%.26–31 Transplant Procedure Conditioning regimen, stem cell harvesting/collection/cryopreservation, and reinfusion are detailed in this section Conditioning Regimen Patients undergoing HCT are subjected to a treatment regimen referred to as a conditioning regimen or preparative regimen prior to infusion of the hematopoietic progenitor cells The purpose of this preparative regimen is multifold In cases of malignant disorders, it provides eradication of disease In addition, the preparative regimen must be immunosuppressive in allogeneic transplantation to allow the donor cells infused to establish themselves in the marrow cavity and overcome host rejection The precise conditioning regimens can include chemotherapy alone or in combination with radiation Numerous regimens have been explored and are dependent on the disease for which the transplant is required and the research interests of the institution performing the transplant Stem Cell Harvesting/Collection/Cryopreservation Stem cells can be collected or harvested from either bone marrow or peripheral blood For patients or donors undergoing bone marrow harvest, general anesthesia or regional anesthesia is given Bone marrow is generally aspirated using special bone marrow harvest needles percutaneously from the posterior iliac crests through numerous passes The amount of marrow taken is based on the size of the recipient If there is a significant size discrepancy between the donor and recipient (recipient larger than donor), the donor may lose a significant amount of blood Donors can be placed on iron therapy after harvest or they can electively store autologous blood ahead of time A newer technique allows for the collected marrow to be processed with removal of red blood cells ... mega-doses of stem cells However, for this to be successful, a majority of the T cells have to be removed from the graft to prevent severe GVHD Unfortunately, this increases the risk for severe... variety of congenital and acquired malignant and nonmalignant disorders Over the years, the name of this procedure has changed with attempts to be more accurate Throughout the literature, it has been... disorders such as autoimmune disorders, metabolic diseases, immunodeficiencies, and hemoglobinopathies Since its inception, the field of pediatric HCT has demonstrated vast improvements in morbidity