Baker, R

Chavda, N

Clark, F

Fielding, AK

Gupta, R

Khwaja, A

Kottaridis, P

Mansour, MR

O'Nions, J

Payne, E

Subhan, M

Thomson, K

Troy-Barnes, E

Wilson, AJ

English

UCL Discovery

Accepted ArticleThis article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bjh.16962 This article is protected by copyright. All rights reserved  1 DR. ANDREW J WILSON (Orcid ID : 0000-0002-0410-3088) 2 DR. JENNY  O'NIONS (Orcid ID : 0000-0002-8917-4546) 3  4  5 Article type      : Letters 6  7  8 Successful remission induction therapy with gilteritinib in a patient with de novo FLT3-mutated 9 acute myeloid leukaemia and severe COVID-19 10  11  12  13 Andrew J. Wilson1,3*, Ethan Troy-Barnes1, Maryam Subhan1, Fiona Clark1, Rajeev Gupta1,2,3, Adele K. 14 Fielding1,2, Panagiotis Kottaridis1, Marc R Mansour1,2, Jenny O’Nions1,3, Elspeth Payne1,2, Naina 15 Chavda3,4, Robert Baker3, Kirsty Thomson1 & Asim Khwaja1,2,3 16  17 *Corresponding author – andrew.wilson19@nhs.net 18 Phone number - +44 203 447 7101 19  20  21 Accepted ArticleThis article is protected by copyright. All rights reserved  22 1 Department of Haematology, University College London Hospital (UCLH), 3rd Floor West, 250 Euston 23 Road, London, UK, NW1 2PG,  24 2 Department of Haematology, University College London Cancer Institute, 74 Huntley Street, 25 London, UK, WC1E 6DD and  26 3 UCLH Specialist Integrated Haematology Malignancy Diagnostic Service, Health Services 27 Laboratories, 1 Mabledon Place, London, UK, NW1 2RA 28  29  30 31 Accepted ArticleThis article is protected by copyright. All rights reserved To the editor, 32 The optimal treatment for patients with newly diagnosed acute myeloid leukaemia (AML) who are 33 infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)/COVID-19 is unknown.1 34 We report the case of a previously fit 27-year-old male who presented with a 3-day history of fever 35 (>39oC), swollen, erythematous elbows and no respiratory symptoms. His white blood count (WBC) 36 was 187×109/L and bone marrow (Figure 1A & 1C) examination revealed normal karyotype AML with 37 a fms related receptor tyrosine kinase 3 (FLT3) internal tandem duplication (ITD), wild-type NPM1 38 and no additional mutations on a next-generation sequencing panel. 39 Hyperleukocytosis was immediately treated with hydroxycarbamide, dexamethasone, rasburicase 40 (for tumour lysis syndrome prophylaxis), and 3 doses of 100mg/m2 cytarabine over the first 48 hours. 41 He received antibiotics to treat febrile neutropenia and cellulitis and although he denied any 42 respiratory symptoms, a combined nasal and pharyngeal swab for SARS-CoV-2 RNA was positive. 43 Ultrasound doppler revealed a lower-limb deep vein thrombosis, bilateral upper-arm superficial 44 thrombophlebitis and coagulation markers were indicative of disseminated intravascular coagulation 45 (DIC; Figure 1B). Given his active SARS-CoV-2 infection and the presence of a FLT3-ITD mutation, he 46 was treated with single-agent gilteritinib, an oral FLT3 inhibitor,2 from day 3. Gilteritinib shows 47 superior efficacy to salvage chemotherapy in relapsed/refractory FLT3-mutated AML,3 with low rates 48 of infection and early mortality, although it is not currently licensed for use in de novo AML. 49 On day 6, he became hypoxic, with hyperpyrexia, rising C-reactive protein (CRP; Figure 1B), and a 50 high-resolution CT scan of the chest (HRCT; Figure 1D) showed changes typical for COVID-19. He was 51 transferred to the intensive care unit on day 7 for continuous positive airway pressure (CPAP) 52 support, but deteriorated further on day 13, requiring emergency intubation due to adult respiratory 53 distress syndrome (ARDS). Dexamethasone was briefly restarted on day 14 to treat early 54 differentiation syndrome.2 He was extubated to CPAP on day 20, however, he experienced a febrile 55 episode associated with seizures on day 22 due to Escherichia coli bacteraemia, which precipitated 56 Accepted ArticleThis article is protected by copyright. All rights reserved re-intubation, vasopressor support and further antibiotics. Gilteritinib was temporarily discontinued 57 for 7 days from day 25 (Figure 1A) due to biochemical features of septic shock-related 58 cardiomyopathy. 59 During the admission, the patient experienced only 5 days of severe neutropenia (<0.5×109/L) and 60 17 days of thrombocytopenia (<50×109/L). Post-induction bone marrow examination showed 61 morphological (Figure 1C) complete remission and a significant reduction in FLT3-ITD allele ratio 62 from 0.66 at diagnosis to 0.07. He received a tracheostomy without incident on day 33. A repeat 63 HRCT on day 39 (Figure 1D) showed extensive changes associated with severe COVID-19. He was 64 decannulated on day 45 and transferred back to the ward for intensive rehabilitation. SARS-CoV-2 65 RNA remained detectable on weekly nasopharyngeal swabs until day 60 when it became 66 undetectable. At the time of writing, he continues on gilteritinib, with a plan to proceed to 67 allogeneic stem cell transplantation when he is physically fit.  68 Though the effects of SARS-CoV-2 infection on patients with AML are largely unknown,1 early 69 evidence suggests that patients with active haematological malignancies and COVID-19 have more 70 severe disease and a higher case fatality rate.4-5 Provisional guidance1,6 recommends delaying AML 71 induction chemotherapy in patients with concurrent COVID-19, an option not possible in this case. 72 Induction mortality rates with intensive chemotherapy in those with hyperleukocytosis can approach 73 30% and such chemotherapy is associated with prolonged pancytopenia (often >3 weeks) and high 74 rates of severe infections.7 We conclude that single-agent gilteritinib can be safely administered and 75 induce remission in patients presenting with de novo FLT3-ITD positive AML. Although further 76 studies are required in this setting, gilteritinib can be considered as a treatment option for patients 77 with FLT3-mutated AML and severe COVID-19, where a prolonged period of chemotherapy-induced 78 pancytopenia could adversely affect outcomes. 79  80 Accepted ArticleThis article is protected by copyright. All rights reserved References 81 1. Paul S, Rausch C, Jain N et al. Treating Leukemia in the Time of COVID-19. Acta Haematol. 82 2020:1-13.  83 2. Levis M and Perl, AE. Gilteritinib: potent targeting of FLT3 mutations in AML. Blood Adv. 84 2020; 4 (6):1178–1191.  85 3. Perl A, Martinelli G, Cortes J et al. Gilteritinib or Chemotherapy for Relapsed or Refractory 86 FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728-1740.  87 4. He W, Chen L, Chen L et al. COVID-19 in persons with haematological cancers. Leukemia. 88 2020, 1–9. Advance online publication.  89 5. Martín‐Moro F, Marquet J, Piris M et al. Survival study of hospitalized patients with 90 concurrent Covid‐19 and haematological malignancies. Br J Haematol. 2020;In Press 91 6. NCRI AML Working Party. 2020. Recommendations for the management of patients with 92 AML during the COVID19 outbreak: a statement from the NCRI AML Working Party [online] 93 Available at: <http://www.cureleukaemia.co.uk/page/news/523/aml-working-party-covid-94 19-recommendations> [Accessed 09/05/2020] 95 7. Nørgaard M, Larsson H, Pedersen G, Schønheyder H, Sørensen H. Risk of bacteraemia and 96 mortality in patients with haematological malignancies. Clinical Microbiology and Infection. 97 2006;12(3):217-223.  98  99 Acknowledgements 100 AW, ETB, MS, FC, RG, AF, PK, MM, JO, EP, KT and AK provided clinical care for the patient and were 101 involved in critically revising the manuscript. NC and RB provided expert assistance in diagnostics 102 and critically revising the manuscript. All authors have approved the final manuscript. 103  104 Accepted ArticleThis article is protected by copyright. All rights reserved Conflicts of Interest  105 AW: personal fees from Novartis, MRM: advisory boards for Janssen, EP: advisory boards for 106 Novartis, Celegene and Takeda, AK: personal fees from Astellas, outside the submitted work. ETB, 107 The other authors have no conflicts of interest to declare.  108   109 Accepted ArticleThis article is protected by copyright. All rights reserved Figure 1 110 Complete blood count parameters are shown in Panel A; white blood count (WBC, reference range 111 3-10×109/L), neutrophils (2-7.5× 09/L) and platelets (150-400×109/L).  Gilteritinib administration 112 (120mg once daily), starting from day 3 onwards, is indicated by blue bars. The patient presented 113 with high d-dimers >80mg/L (range<0.5mg/L; Panel B) and hypofibrinogenemia (range 1.5-4g/L), 114 followed by a hyperfibrinogenemic stage during which C-reactive protein (CRP; range <5mg/L, Panel 115 B) peaked. Mild tumour lysis syndrome developed with a near doubling of baseline creatinine (range 116 66-112 µmol/L; Panel B). Morphological analysis of the bone marrow smear at diagnosis (Panel C, 117 top pane) showed heavy infiltration by myelomonocytic blasts, which were positive for CD34, 118 CD117, HLA-DR, CD33, CD15, CD38, cytoplasmic myeloperoxidase and weakly positive for CD7 by 119 flow cytometry (not shown). The post-induction bone marrow smear showed morphological (Panel 120 C, bottom pane) and flow cytometric complete remission. The initial high-resolution CT (HRCT) scan 121 on day 6 (Panel D, top pane) displays patchy infiltrates with extensive patchy areas of ground glass 122 opacification and ‘crazy paving’ pattern, typical of severe COVID-19. Repeat HRCT at day 39 (bottom 123 pane) showed widespread ground glass opacification, as well as areas of consolidation and a 124 progressive left sided pleural effusion. 125 Accepted Article

Successful remission induction therapy with gilteritinib in a patient with de novo FLT3-mutated acute myeloid leukaemia and severe COVID-19

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Successful remission induction therapy with gilteritinib in a patient with de novo FLT3-mutated acute myeloid leukaemia and severe COVID-19

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