In the realm of hematologic disorders, acute leukemia is approached as an emergent disease given the multitude of complications and challenges that present both as a result of inherent disease pathology and adverse events associated with antineoplastic therapies and interventions. The heavy burden of leukemic cells may lead to complications including tumor lysis syndrome, hyperleukocytosis, leukostasis, and differentiation syndrome, and the initiation of treatment can further exacerbate these effects. Capillary leak syndrome is observed as a result of antineoplastic agents used in acute leukemia, and L-asparaginase, a bacterial-derived enzyme, has a unique side effect profile including association with thrombosis. Thrombohemorrhagic syndrome and malignancy-associated thrombosis are also commonly observed complications due to direct disequilibrium in coagulant and anticoagulant factors. Due to inherent effects on the white blood cell milieu, leukemia patients are inherently immunocompromised and vulnerable to life-threatening sepsis. Lastly, the advents of newer therapies such as chimeric antigen receptor (CAR) T-cells have clinicians facing the management of related toxicities on unfamiliar territory. This review aims to discuss these acute leukemia-associated complications, their pathology, and management recommendations.
PuriISharmaDGunturuKS, et al.Diagnosis and management of tumor lysis syndrome. J Community Hosp Intern Med Perspect. 2020 Jun 14;10(3):269–272. doi:10.1080/20009666.2020.1761185
2.
CairoMSBishopM. Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol. 2004;127(1):3–11.
3.
HowardSCJonesDPPuiCH. The tumor lysis syndrome. N Engl J Med. 2011 May 12;364(19):1844–1854. doi:10.1056/NEJMra0904569
FeigDIKangDHJohnsonRJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811–1821.
6.
ShimadaMJohnsonRJMayWS, et al.A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome. Nephrol Dial Transplant. 2009;24(10):2960–2964.
7.
EjazAAMuWKangDH, et al.Could uric acid have a role in acute renal failure?Clin J Am Soc Nephrol. 2007;2(1):16–21.
8.
HijiyaNMetzgerMLPoundsS, et al.Severe cardiopulmonary complications consistent with systemic inflammatory response syndrome caused by leukemia cell lysis in childhood acute myelomonocytic or monocytic leukemia. Pediatr Blood Cancer. 2005;44(1):63–69.
9.
NakamuraMOdaSSadahiroT, et al.The role of hypercytokinemia in the pathophysiology of tumor lysis syndrome (TLS) and the treatment with continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF). Transfus Apher Sci. 2009;40(1):41–47.
10.
SoaresMFeresGASalluhJI. Systemic inflammatory response syndrome and multiple organ dysfunction in patients with acute tumor lysis syndrome. Clinics (Sao Paulo). 2009;64(5):479–481.
11.
CoiffierBAltmanAPuiCH, et al.Guidelines for the management of pediatric and adult tumor lysis syndrome: An evidence-based review. J Clin Oncol. 2008;26(16):2767.
12.
CairoMSCoiffierBReiterA, et al.Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: An expert TLS panel consensus. Br J Haematol. 2010;149:578.
13.
CairoMSCoiffierBReiterA, et al.Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: An expert TLS panel consensus. Br J Haematol. 2010;149(4):578–586.
14.
Abu-AlfaAKYounesA. Tumor lysis syndrome and acute kidney injury: Evaluation, prevention, and management. Am J Kidney Dis. 2010;55(5 Suppl 3):S1–S13.
15.
JonesGLWillAJacksonGH, et al.British Committee for standards in haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British committee for standards in haematology. Br J Haematol. 2015;169(5):661–671.
16.
Lopez-OlivoMAPrattGPallaSL, et al.Rasburicase in tumor lysis syndrome of the adult: A systematic review and meta-analysis. Am J Kidney Dis. 2013;62(3):481–492.
17.
BosePQubaiahO. A review of tumour lysis syndrome with targeted therapies and the role of rasburicase. J Clin Pharm Ther. 2011;36(3):299–326.
18.
MayerMDKhosravanRVernilletL, et al.Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005;12(1):22–34.
19.
McKeeLCCollinsRD. Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia. Medicine (Baltimore). 1974;53(6):463–478.
20.
van BuchemMAte VeldeJWillemzeRSpaanderPJ. Leucostasis, an underestimated cause of death in leukaemia. Blut. 1988;56(1):39–44.
21.
SoaresFALandellGACardosoMC. Pulmonary leukostasis without hyperleukocytosis: A clinicopathologic study of 16 cases. Am J Hematol. 1992;40(1):28–32.
22.
AliAMMirrakhimovAEAbboudCNCashenAF. Leukostasis in adult acute hyperleukocytic leukemia: A clinician's digest. Hematol Oncol. 2016 Jun;34(2):69–78. doi:10.1002/hon.2292
23.
CuttnerJConjalkaMSReillyM, et al.Association of monocytic leukemia in patients with extreme leukocytosis. Am J Med. 1980;69(4):555–558.
24.
DaverNKantarjianHMarcucciG, et al.Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis. Br J Haematol. 2015;168(5):646–653.
25.
PorcuPFaragSMarcucciGCatalandSRKennedyMSBissellM. Leukocytoreduction for acute leukemia. Ther Apher. 2002;6(1):15–23.
26.
PorcuPCripeLDNgEW, et al.Hyperleukocytic leukemias and leukostasis: A review of pathophysiology, clinical presentation, and management. Leuk Lymphoma. 2000;39(1-2):1–18.
27.
LeisJFPrimackSLSchubachSECurtinPTDrukerBJMaziarzRT. Management of life-threatening pulmonary leukostasis with single agent imatinib mesylate during CML myeloid blast crisis. Haematologica. 2004;89(9):ECR30.
DurzyńskiTKonopkaLTraczykZ. Leukostasis syndrome in a case of chronic lymphocytic leukemia. Pol Merkur Lekarski. 1999;6(31):30–31.
30.
CukiermanTGattMELibsterDGoldschmidtNMatznerY. Chronic lymphocytic leukemia presenting with extreme hyperleukocytosis and thrombosis of the common femoral vein. Leuk Lymphoma. 2002;43(9):1865–1868.
31.
StuckiARivierASGikicM, et al.Endothelial cell activation by myeloblasts: Molecular mechanisms of leukostasis and leukemic cell dissemination. Blood. 2001;97(7):2121.
32.
AzoulayEFieuxFMoreauD, et al.Acute monocytic leukemia presenting as acute respiratory failure. Am J Respir Crit Care Med. 2003;167(10):1329–1333.
33.
GanzelCBeckerJMintzPDLazarusHMRoweJM. Hyperleukocytosis, leukostasis and leukapheresis: Practice management. Blood Rev. 2012;26(3):117–122.
34.
ThiébautAThomasXBelhabriAAnglaretBArchimbaudE. Impact of pre-induction therapy leukapheresis on treatment outcome in adult acute myelogenous leukemia presenting with hyperleukocytosis. Ann Hematol. 2000;79(9):501–506.
35.
KasnerMTLauryAKasnerSECarrollMLugerSM. Increased cerebral blood flow after leukapheresis for acute myelogenous leukemia. Am J Hematol. 2007;82(12):1110–1112.
36.
GilesFJShenYKantarjianHM, et al.Leukapheresis reduces early mortality in patients with acute myeloid leukemia with high white cell counts but does not improve long-term survival. Leuk Lymphoma. 2001;42(1–2):67–73.
37.
BugGAnargyrouKTonnT, et al.Impact of leukapheresis on early death rate in adult acute myeloid leukemia presenting with hyperleukocytosis. Transfusion. 2007;47(10):1843–1850.
38.
PorcuPDanielsonCFOraziAHeeremaNAGabigTGMcCarthyLJ. Therapeutic leukapheresis in hyperleucocytic leukaemias: Lack of correlation between degree of cytoreduction and early mortality rate. Br J Haematol. 1997;98(2):433–436.
39.
OberoiSLehrnbecherTPhillipsB, et al.Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: A systematic review and meta-analysis. Leuk Res. 2014;38(4):460–468.
40.
MottalNIssaNDumasPY, et al.Reduce mortality and morbidity in acute myeloid leukemia with hyperleukocytosis with early admission in intensive care unit: A retrospective analysis. J Hematol. 2020 Dec;9(4):109–115. doi:10.14740/jh691
BirendraKCDiNardoCD. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk. 2016;16(8):460–465.
47.
FathiATDiNardoCDKlineI, et al.Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: Analysis of a phase 1/2 study. JAMA Oncol. 2018;4(8):1106–1110.
48.
FathiATDinardoCDKlineI, et al.Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2). J Clin Oncol. 2017;35(15_suppl):7015.
49.
WangFTravinsJDeLaBarreB, et al.Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013;340(6132):622–626.
50.
IssaGCAldossIDiPersioJF, et al.The menin inhibitor SNDX-5613 (revumenib) leads to durable responses in patients (pts) with KMT2A-rearranged or NPM1 mutant AML: Updated results of a phase (Ph) 1 study. Blood. 2022;140(Supplement 1):150–152.
51.
MontesinosPBerguaJMVellengaE, et al.Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: Characteristics, outcome, and prognostic factors. Blood. 2009;113(4):775–783.
52.
NorsworthyKJMulkeyFScottEC, et al.Differentiation syndrome with ivosidenib and enasidenib treatment in patients with relapsed or refractory IDH-mutated AML: A U.S. food and drug administration systematic analysis. Clin Cancer Res. 2020;26(16):4280–4288.
53.
Lo-CocoFAvvisatiGVignettiM, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–121.
54.
FathiATDiNardoCDPollyeaDA, et al.AG221-C-001 study investigators. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: Analysis of a phase 1/2 study. JAMA Oncol. 2018 Aug 1;4(8):1106–1110. doi:10.1001/jamaoncol.2017.4695
55.
ShinJILeeKHLeeIR, et al.Systemic capillary leak syndrome (Clarkson syndrome) in cancer patients: A systematic review. J Clin Med. 2018;7(11):418.
56.
KapoorPGreippPTSchaeferEW, et al.Idiopathic systemic capillary leak syndrome (Clarkson’s disease): The Mayo clinic experience. Mayo Clin Proc. 2010;85(10):905–912.
57.
IzzedineHMathianAAmouraZNgJHJhaveriKD. Anticancer drug-induced capillary leak syndrome. Kidney Int Rep. 2022 Feb 25;7(5):945–953. doi:10.1016/j.ekir.2022.02.014
58.
JeongGHLeeKHLeeIR, et al.Incidence of capillary leak syndrome as an adverse effect of drugs in cancer patients: a systematic review and meta-analysis. J Clin Med. 2019;8(2):143.
59.
XieZGhoshCCPatelR, et al.Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome). Blood. 2012;119(12):4321–4332.
60.
LesterhuisWJRenningsAJLeendersWP, et al.Vascular endothelial growth factor in systemic capillary leak syndrome. Am J Med. 2009;122(6):e5–e7.
61.
KinoshitaYKasaokaSFujitaM, et al.Synchronized changes in serum vascular endothelial growth factor during the clinical course of chronic systemic capillary leak syndrome. Intern Med. 2010;49(8):791–794.
62.
XieZChanEYinY, et al.Inflammatory markers of the systemic capillary leak syndrome (Clarkson disease). J Clin Cell Immunol. 2014;5:1000213.
WinklerUJensenMManzkeO, et al.Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood. 1999;94(7):2217–2224.
65.
SpitzerTR. Engraftment syndrome: Double-edged sword of hematopoietic cell transplants. Bone Marrow Transplant. 2015;50(4):469–475.
66.
LuesinkMJansenJH. Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia. Br J Haematol. 2010;151(3):209–220.
67.
MertzPLebrun-VignesBSalemJEArnaudL. Characterizing drug-induced capillary leak syndromes using the World Health Organization VigiBase. J Allergy Clin Immunol. 2019;143(1):433–436.
68.
AlkharabshehOFrankelAE. Clinical activity and tolerability of SL-401 (tagraxofusp): Recombinant diphtheria toxin and interleukin-3 in hematologic malignancies. Biomedicines. 2019 Jan 5;7(1):6. doi:10.3390/biomedicines7010006
69.
QinHVlaminckBOwoyemiI, et al.Successful treatment of pembrolizumab-induced severe capillary leak syndrome and lymphatic capillary dysfunction. Mayo Clin Proc Innov Qual Outcomes. 2021;5(3):670–674.
70.
MutchlerSMKleymanTR. New insights regarding epithelial Na+ channel regulation and its role in the kidney, immune system and vasculature. Curr Opin Nephrol Hypertens. 2019;28(2):113–119.
71.
PemmarajuNKonoplevaM. Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. Blood Adv. 2020 Aug 25;4(16):4020–4027. doi:10.1182/bloodadvances.2019000173
72.
AulagnonFLapidusNCanetE, et al.Acute kidney injury in adults with hemophagocytic lymphohistiocytosis. Am J Kidney Dis. 2015;65(6):851–859.
73.
HorstedFWestJGraingeMJ. Risk of venous thromboembolism in patients with cancer: A systematic review and meta-analysis. PLoS Med. 2012;9(7):e1001275.
74.
BarbuiTFinazziGFalangaA. The management of bleeding and thrombosis in acute leukemia and chronic myeloproliferative disorders. In: HendersonESListerTAGreavesMF, eds. Leukemia. 7th ed. WB Saunders Company; 2001:363–382.
LadDJainAVarmaS. Complications and management of coagulation disorders in leukemia patients. Blood Lymphat Cancer. 2017 Sep 18;7:61–72. doi:10.2147/BLCTT.S125121
77.
IsacsonS. Effect of prednisolone on the coagulation and fibrinolytic systems. Scand J Haematol. 1970;7(3):212–216. doi:10.1111/j.1600-0609.1970.tb01890.x
78.
GiordanoPDelVecchioGCSantoroN, et al.Thrombin generation in children with acute lymphoblastic leukemia: Effect of leukemia immun- ophenotypic subgroups. Pediatr Hematol Oncol. 2000;17(8):667–672.
79.
PuiCH. Childhood leukemias. N Engl J Med. 1995 Jun 15;332(24):1618–1630. doi:10.1056/NEJM199506153322407
80.
PourhassanHDouerDPullarkatVAldossI. Asparaginase: How to better manage toxicities in adults. Curr Oncol Rep. 2023 Jan;25(1):51–61. doi:10.1007/s11912-022-01345-6
81.
AldossIDouerDBehrendtCE, et al.Toxicity profile of repeated doses of PEGasparaginase incorporated into a pediatric-type regimen for adult acute lymphoblastic leukemia. Eur J Haematol. 2016;96(4):375–380.
82.
UnderwoodBZhaoQWalkerAR, et al.Incidence of venous thrombosis after peg-asparaginase in adolescent and young adults with acute lymphoblastic leukemia. Int J Hematol Oncol. 4 Sep. 2020;9(3):IJH28.
83.
Nowak-GöttUHeineckeAvon KriesRNurnbergerWMunchowNJunkerR. Thrombotic events revisited in children with acute lymphoblastic leukemia: Impact of concomitant Escherichia coli asparaginase/prednisone administration. Thromb Res. 2001;103(3):165–172. doi:10.1016/S0049-3848(01)00286-9
84.
YanadaMMatsushitaTSuzukiM, et al.Disseminated intravascular coagulation in acute leukemia: Clinical and laboratory features at presentation. Eur J Haematol. 2006;77(4):282–287.
85.
UchiumiHMatsushimaTYamaneA, et al.Prevalence and clinical characteristics of acute myeloid leukemia associated with disseminated intravascular coagulation. Int J Hematol. 2007;86(2):137–142.
86.
MenellJSCesarmanGMJacovinaATMcLaughlinMALevEAHajjarKA. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med. 1999;340(13):994–1004.
87.
KwaanHCWangJWeissI. Expression of receptors for plasminogen activators on endothelial cell surface depends on their origin. J Thromb Haemost. 2004;2(2):306–312.
88.
LavalléeVPMarquisMBordeleauME, et al.Transcriptional landscape of APL identifies aberrant podoplanin expression as a defining feature and missing link for the bleeding disorder of this disease. Blood. 2016;128(22):1075.
89.
SanzMAGrimwadeDTallmanMS, et al.Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875–1891.
90.
DesboroughMHadjinicolaouAVChaimaniA, et al.Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: A meta-analysis and systematic review. Cochrane Database Syst Rev. 2016;10(10):CD012055.
91.
EstcourtLJDesboroughMBrunskillSJ, et al.Antifibrinolytics (lysine analogues) for the prevention of bleeding in people with haematological disorders. Cochrane Database Syst Rev. 2016;3(3):CD009733.
92.
Martí-CarvajalAJAnandVSolàI. Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. Cochrane Database Syst Rev. 2015;2015(6):CD008562.
93.
ThachilJFalangaALeviM, et al.Management of cancer-associated disseminated intravascular coagulation: Guidance from the SSC of the ISTH. J Thromb Haemost. 2015;13(4):671–675.
94.
KeyNSKhoranaAAKudererNM, et al.Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38(5):496–520.
95.
StevensSMWollerSCKreuzigerLB, et al.Antithrombotic therapy for VTE disease: Second update of the CHEST guideline and expert panel report. Chest. 2021;160(6):e545–e608.
96.
StreiffMBHolmstromBAshraniA, et al.Cancer-associated venous thromboembolic disease, version 1.2015. J Natl Compr Canc Netw. 2015;13(9):1079–1095.
97.
FargeDDebourdeauPBeckersM, et al.International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost. 2013;11(1):56–70.
98.
StreiffMBHolmstromBAngeliniD, et al.NCCN guidelines insights: Cancer-associated venous thromboembolic disease, version 2.2018. J Natl Compr Canc Netw. 2018;16(11):1289–1303.
99.
KhoranaAANobleSLeeAYY, et al.Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16(9):1891–1894.
100.
KonstantinidesSVMeyerGBecattiniC, et al.2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019;54(3):1901647.
101.
FargeDFrereCConnorsJM, et al.2019 International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol. 2019;20(10):e566–e581.
102.
LymanGHCarrierMAyC, et al.American Society of Hematology 2021 guidelines for management of venous thromboembolism: Prevention and treatment in patients with cancer. Blood Adv. 2021;5(4):927–974.
103.
FargeDFrereCConnorsJM, et al.2022 International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19. Lancet Oncol. 2022;23(7):e334–e347.
104.
AgnelliGBecattiniCMeyerG, et al.Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382(17):1599–1607.
105.
AgnelliGMuñozAFrancoL, et al.Apixaban and dalteparin for the treatment of venous thromboembolism in patients with different sites of cancer. Thromb Haemost. 2022;122(5):796–807.
106.
GraceRFDahlbergSENeubergD, et al.The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol. 2011;152(4):452–459.
107.
RankCUToftNTuckuvieneR, et al.Thromboembolism in acute lymphoblastic leukemia: Results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years. Blood. 2018;131(22):2475–2484.
108.
GoyalGBhattVR. L-asparaginase and venous thromboembolism in acute lymphocytic leukemia. Future Oncol. 2015;11(17):2459–2470. doi:10.2217/fon.15.114. Epub 2015 Aug 14.
109.
SuiJZhangYYangL, et al.Successful treatment with rivaroxaban of cerebral venous thrombosis and bone marrow necrosis induced by pegaspargase: A case report and literature review. Medicine (Baltimore). 2017;96(46):e8715.
110.
PlanderMSzendreiTBodoIIvanyiJL. Successful treatment with rivaroxaban of an extended superficial vein thrombosis in a patient with acquired antithrombin deficiency due to Peg-asparaginase treatment. Ann Hematol. 2015;94(7):1257–1258.
111.
TalamoLDouvasMMacikBGOrnanD. Successful treatment with apixaban of sinus venous thrombosis due to pegylated asparaginase in a young adult with T cell acute lymphoblastic leukemia: Case report and review of management. Ann Hematol. 2017;96(4):691–693.
112.
RaskobGEvan EsNVerhammeP, et al.Edoxaban for the treatment of cancer associated venous thromboembolism. N Engl J Med. 2018;378(7):615–624.
113.
WilliamsMDBraunLACooperLM, et al.Hospitalized cancer patients with severe sepsis: Analysis of incidence, mortality, and associated costs of care. Crit Care. 2004;8(5):R291–R298.
114.
LemialeVPonsSMirouseA, et al.Sepsis and septic shock in patients with malignancies: A Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique study. Crit Care Med. 2020;48(6):822–829.
115.
ManjappacharNKCuencaJARamírezCM, et al.Outcomes and predictors of 28-day mortality in patients with hematologic malignancies and septic shock defined by sepsis-3 criteria. J Natl Compr Canc Netw. 2022 Jan;20(1):45–53. doi:10.6004/jnccn.2021.7046
116.
AzoulayEMokartDPèneF, et al.Outcomes of critically ill patients with hematologic malignancies: Prospective multicenter data from France and Belgium—A Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique study. J Clin Oncol. 2013;31(22):2810–2818.
117.
AzoulayÉSoaresMLenglinéÉ. Preempting critical care services for patients with hematological malignancies. Intensive Care Med. 2021;47(10):1140–1143.
118.
GudiolCAlbasanz-PuigACuervoGCarratalàJ. Understanding and managing sepsis in patients with cancer in the era of antimicrobial resistance. Front Med (Lausanne). 2021 Mar 31;8:636547. doi:10.3389/fmed.2021.636547
119.
LemialeVPonsSMirouseA, et al.Sepsis and septic shock in patients with malignancies: A groupe de recherche respiratoire en reanimation oncohematologique study. Crit Care Med. 2020;48(6):822–829.
120.
Roze des OrdonsALChanKMirzaITownsendDRBagshawSM. Clinical characteristics and outcomes of patients with acute myelogenous leukemia admitted to intensive care: a case-control study. BMC Cancer. 2010;10:516.
121.
BodeyGPBuckleyMSatheYSFreireichEJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966;64(2):328–340.
122.
SchimpffSSatterleeWYoungVMSerpickA. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med. 1971;284(19):1061–1065.
123.
MarínMGudiolCArdanuyC, et al.Factors influencing mortality in neutropenic patients with haematologic malignancies or solid tumours with bloodstream infection. Clin Microbiol Infect. 2015;21(6):583–590.
124.
VincentJLMorenoRTakalaJ, et al.The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the European society of intensive care medicine. Intensive Care Med. 1996;22(7):707–710.
125.
RosolemMMRabelloLSLisboaT, et al.Critically ill patients with cancer and sepsis: Clinical course and prognostic factors. J Crit Care. 2012;27(3):301–307.
126.
TorresVBAzevedoLCSilvaUV, et al.Sepsis-associated outcomes in critically ill patients with malignancies. Ann Am Thorac Soc. 2015;12(8):1185–1192.
127.
AverbuchDOraschCCordonnierC, et al.European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: Summary of the 2011 4th European conference on infections in leukemia. Haematologica. 2013;98:1826.
128.
PaulMLadorAGrozinsky-GlasbergSLeiboviciL. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2014;2014(1):CD003344.
129.
OngDSYFrenckenJFKlein KlouwenbergPMC, et al.Short-course adjunctive gentamicin as empirical therapy in patients with severe sepsis and septic shock: A prospective observational cohort study. Clin Infect Dis. 2017;64(12):1731–1736.
130.
HakkiMLewisJSII. Ceftolozane-tazobactam therapy for multidrug-resistant Pseudomonas aeruginosa infections in patients with hematologic malignancies and hematopoietic-cell transplant recipients. Infection. 2018;46(3):431–434.
131.
Fernández-CruzAAlbaNSemiglia-ChongMA, et al.A case-control study of real-life experience with ceftolozane-tazobactam in patients with hematologic malignancy and Pseudomonas aeruginosa infection. Antimicrob Agents Chemother. 2019;63(2):e02340–e02318. doi:10.1128/AAC.02340-18
132.
AitkenSLKontoyiannisDPDePomboAM, et al.Use of ceftolozane/tazobactam in the treatment of multidrug-resistant Pseudomonas aeruginosa bloodstream infection in a pediatric leukemia patient. Pediatr Infect Dis J. 2016;35(9):1040–1042.
133.
SoWShurkoJGalegaRQuilitzRGreeneJNLeeGC. Mechanisms of high-level ceftolozane/tazobactam resistance in Pseudomonas aeruginosa from a severely neutropenic patient and treatment success from synergy with tobramycin. J Antimicrob Chemother. 2019;74(1):269–271.
134.
CastónJJLacort-PeraltaIMartín-DávilaP, et al.Clinical efficacy of ceftazidime/avibactam versus other active agents for the treatment of bacteremia due to carbapenemase-producing Enterobacteriaceae in hematologic patients. Int J Infect Dis. 2017;59:118–123.
135.
MetafuniECriscuoloMSpanuTSicaS. Ceftazidime-avibactam for gram-negative multidrug-resistant bacteria in hematological patients: A single-center experience. Ann Hematol. 2019;98(6):1495–1497.
136.
HobsonCABonacorsiSFahdM, et al.Successful treatment of bacteremia due to NDM-1-producing morganella morganii with aztreonam and ceftazidime-avibactam combination in a pediatric patient with hematologic malignancy. Antimicrob Agents Chemother. 2019;63(2):e02463–18. doi:10.1128/AAC.02463-18
137.
RhodesAEvansLEAlhazzaniW, et al.Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–377.
138.
Aguilar-GuisadoMEspigadoIMartín-PeñaA, et al.Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (how long study): An open-label, randomised, controlled phase 4 trial. Lancet Haematol. 2017;4(12):e573–e583.
139.
SieversSWatsonGJohncySAdkinsS. Recognizing and grading CAR T-cell toxicities: An advanced practitioner perspective. Front Oncol. 2020 Jun 24;10:885. doi:10.3389/fonc.2020.00885
140.
NeelapuSSLockeFLBartlettNL, et al.Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–2544.
141.
HayKAHanafiLALiD, et al.Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295–2306.
142.
BrudnoJNKochenderferJN. Toxicities of chimeric antigen receptor T cells: Recognition and management. Blood. 2016;127(26):3321–3330.
143.
LeeDWGardnerRPorterDL, et al.Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–195.
144.
MaudeSLFreyNShawPA, et al.Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517. doi:10.1056/NEJMoa1407222
145.
LeeDWSantomassoBDLockeFL, et al.ASTCT Consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transpl. 2019;25(4):625–638.
146.
JainTBarMKansagraAJ, et al.Use of chimeric antigen receptor T cell therapy in clinical practice for relapsed/refractory aggressive B cell non-hodgkin lymphoma: An expert panel opinion from the American Society for transplantation and cellular therapy. Biol Blood Marrow Transplant. 2019;25:2305–2321.
147.
FreyNPorterD. Cytokine release syndrome with chimeric antigen receptor T cell therapy. Biol Blood Marrow Transplant. 2019;25(12):e123–e127.
148.
HillJALiDHayKA, et al.Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018;131(1):121–130.
149.
ParkJHRiviereIGonenM, et al.Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–459.
150.
TeacheyDTLaceySFShawPA, et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664–679.
151.
HunterBDJacobsonCA. CAR T-cell associated neurotoxicity: Mechanisms, clinicopathologic correlates, and future directions. J Natl Cancer Inst. 2019;111(7):646–654.
152.
NeelapuSSTummalaSKebriaeiP, et al.Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62.
153.
KarschniaPJordanJTForstDA, et al.Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood. 2019;133:2212–2221.
154.
GustJHayKAHanafiLA, et al.Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–1419.
155.
SantomassoBDParkJHSalloumD, et al.Clinical and biologic correlates of neurotoxicity associated with CAR T cell therapy in patients with B-cell acute lymphoblastic leukemia (B-ALL). Cancer Discov. 2018;8(8):958–971.
156.
SchusterSJSvobodaJChongEA, et al.Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–2554.
157.
Shimabukuro-VornhagenAGodelPSubkleweM, et al.Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56.
HaydenAParkSGiustiniDLeeAYChenLY. Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood Rev. 2016;30(6):411–420.
160.
YáñezLAlarcónASánchez-EscamillaMPeralesMA. How I treat adverse effects of CAR-T cell therapy. ESMO Open. 2020 Aug;4(Suppl 4):e000746. doi:10.1136/esmoopen-2020-000746
161.
KhadkaRHSakemuraRKenderianSSJohnsonAJ. Management of cytokine release syndrome: An update on emerging antigen-specific T cell engaging immunotherapies. Immunotherapy. 2019;11(10):851–857.
162.
DavilaMLRiviereIWangX, et al.Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25.
163.
BrentjensRJDavilaMLRiviereI, et al.CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38.
164.
NeelapuSSTummalaSKebriaeiP, et al.Toxicity management after chimeric antigen receptor T cell therapy: One size does not fit ‘ALL’. Nat Rev Clin Oncol. 2018;15(4):218.
165.
NishimotoNTeraoKMimaTNakaharaHTakagiNKakehiT. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–3964.
166.
TurtleCJHayKAHanafiLA, et al.Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35(26):3010–3020.
167.
ChenFTeacheyDTPequignotE, et al.Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods. 2016;434:1–8. Published online ahead of print April 3, 2016.
168.
GruppSAKalosMBarrettD, et al.Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–1518.
169.
FranquizMJShortNJ. Blinatumomab for the treatment of adult B-cell acute lymphoblastic leukemia: Toward a new era of targeted immunotherapy. Biologics. 2020 Feb 14;14:23–34.
170.
ToppMSGökbugetNSteinAS, et al.Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: A multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66.
171.
OjemolonPEKalidindiSAhlbornTAAihieOPAwoyomiMI. Cytokine release syndrome following blinatumomab therapy. Cureus. 2022 Jan 25;14(1):e21583.
