ORIGINAL RESEARCH Managing hematological cancer patients during the COVID-19 pandemic: an ESMO-EHA Interdisciplinary Expert Consensus C. Buske1*, M. Dreyling2, A. Alvarez-Larrán3, J. Apperley4, L. Arcaini5,6, C. Besson7,8, L. Bullinger9,10, P. Corradini11, M. Giovanni Della Porta12,13, M. Dimopoulos14, S. D’Sa15, H. T. Eich16, R. Foà17, P. Ghia18, M. G. da Silva19, J. Gribben20, R. Hajek21, C. Harrison22, M. Heuser23, B. Kiesewetter24, J. J. Kiladjian25, N. Kröger26, P. Moreau27, J. R. Passweg28, F. Peyvandi29,30, D. Rea31, J.-M. Ribera32, T. Robak33, J. F. San-Miguel34, V. Santini35, G. Sanz36,37, P. Sonneveld38, M. von Lilienfeld-Toal39,40, C. Wendtner41, G. Pentheroudakis42 & F. Passamonti43* 1 Institute of Experimental Cancer Research, Department of Internal Medicine III, University Hospital Ulm, Ulm; 2Department of Medicine III at LMU Hospital, Munich, Germany; 3Hematology Department, Hospital Clínic, IDIBAPS, Barcelona, Spain; 4Centre for Haematology, Imperial College London, Hammersmith Hospital, London, UK; 5Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia; 6Department of Molecular Medicine, University of Pavia, Pavia, Italy; 7Service d’Hématologie Oncologie, Centre Hospitalier de Versailles, Le Chesnay; 8UVSQ, Inserm, CESP, Villejuif, France; 9Department of Hematology, Oncology, and Tumorimmunology, Campus Virchow Klinikum, Berlin; 10Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 11Hematology Division, University of Milan, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan; 12Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan; 13Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; 14Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 15UCLH Centre for Waldenström and Neurohaematology, University College London Hospitals NHS Foundation Trust, London, UK; 16Department of Radiation Oncology, University of Muenster, Münster, Germany; 17Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome; 18Strategic Research Program on Chronic Lymphocytic Leukemia and Laboratory of B Cell Neoplasia, Division of Molecular Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy; 19Department Of Hematology, Portuguese Institute of Oncology, Lisbon, Portugal; 20Barts Cancer Institute, Queen Mary University of London, London, UK; 21Department of Hematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 22Clinical Director - Haematology, Haemostasis, Palliative Care, Cellular Pathology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 23Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hanover, Germany; 24 Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria; 25Université de Paris, APHP, Hôpital Saint-Louis, Centre d’Investigations Cliniques, Paris, France; 26Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 27Hematology Department, University Hospital Hotel-Dieu, Nantes, France; 28Hematology Division, Basel University Hospital, Basel, Switzerland; 29Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan; 30Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; 31University Medical Department of Hematology and Immunology, France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC), Hôpital Saint-Louis, Paris, France; 32Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain; 33Department of Hematology, Medical University of Lodz, Lodz, Poland; 34Clínica Universidad de Navarra (CUN), Centro de Investigación Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, Spain; 35MDS Unit, Hematology, DMSC, AOUC, University of Florence, Florence, Italy; 36Hematology Department, Hospital Univesitario y Politecnico La Fe, Valencia; 37CIBERONC, IS Carlos III, Madrid, Spain; 38Erasmus MC Cancer Institute, Department of Haematology, Rotterdam, The Netherlands; 39Department of Hematology and Medical Oncology, University Hospital Jena, Jena; 40Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena; 41Munich Clinic Schwabing, Academic Teaching Hospital, Ludwig-Maximilian University, Munich, Germany; 42Scientific and Medical Division, European Society for Medical Oncology, Lugano, Switzerland; 43Department of Medicine and Surgery, University of Insubria, Varese, Italy Available online 28 January 2022 Background: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. Methods: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. *Correspondence to: Prof. Christian Buske, Institute of Experimental Cancer Research, University Hospital Ulm, Germany, Albert-Einstein-Allee 23, 89081 Ulm, Germany. Tel: þ49-73150065801/888 E-mail: christian.buske@uni-ulm.de (C. Buske). *Prof. Francesco Passamonti, Department of Medicine and Surgery, University of Insubria, Varese, Ospedale di Circolo, Varese, Viale Borri, 57, Varese, Italy. Tel: þ39-332-393-648 E-mail: Francesco.Passamonti@asst-settelaghi.it (F. Passamonti). 2059-7029/© 2022 The Authors. Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Volume 7 - Issue 2 - 2022 https://doi.org/10.1016/j.esmoop.2022.100403 1 ESMO Open C. Buske et al. Results and conclusion: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic. Key words: COVID-19, hematological malignancies, consensus manuscript INTRODUCTION except in patients receiving Janus kinase (JAK) inhibitors The novel SARS-CoV-2 led to a worldwide pandemic in (near 60%).30 2020 and has become a major global health concern Based on the known frailty of HMs, the rapidly changing affecting >220 million people and causing >4.5 million situation during the pandemic with its multiple infectious deaths worldwide until September 2021 (https:// waves and the spread of distinct virus variants worldwide, coronavirus.jhu.edu/map.html). COVID-19 is a systemic and the highly divergent situation of the health system in disease with most of the patients presenting with mild or different countries, management of HM patients has focused moderate symptoms. Up to 5%-10%, however, will present on avoiding hospital stays and reducing immunocomprom- severe or life-threatening disease course and dysfunctions, ising treatments, up to delaying initiation of anticancer and complications can persist for at least 6 months after treatment if thought feasible. Most of this decision making diagnosis.1,2 was based on little evidence, raising many open questions Because of immunosuppression, the potential threat of with regard to the optimal care for HM during the pandemic. COVID-19 to cancer patients is significant and a higher Thus, there is an urgent need for consensus statements on mortality rate has been documented for multiple cancers how to clinically manage HM patients in this unprecedented worldwide.3 Immunosuppression is particularly evident in situation of the COVID-19 pandemic. To provide guidance for hematological malignancies (HMs) such as leukemias, the clinical care in HM, a large interdisciplinary and inter- myelodysplastic syndromes (MDS), myeloproliferative neo- national committee on behalf of the European Society for plasms (MPNs), lymphomas, and multiple myeloma (MM). Medical Oncology (ESMO) and European Hematology Asso- This is based on the fact that malignant transformation in ciation (EHA) established an international and multidisci- HM affects immunocompetent cells themselves and/or that plinary group of experts to discuss clinical evidence anticancer treatments targeting the transformed immune (consensus) and to provide expert advice on areas of con- cells regularly compromise their normal healthy counter- troversy in the management of HM patients in the parts. Based on large cohorts,4,5 international registries,6 pandemic. By this, a consensus was developed offering a and meta-analysis,7 the mortality of COVID-19 in HM is comprehensive set of recommendations including a high with w35% of patients dying with documented SARS- consensus on COVID-19 diagnosis, treatment, and mitigation CoV-2 infection. Mortality was also assessed in distinct HM strategies for the heterogeneous group of HMs. This concise as MM,8 chronic lymphocytic leukemia (CLL),9 non-Hodg- consensus statement will help to optimize clinical manage- kin’s lymphoma (NHL),10 and in patients who received he- ment in HMs and support multidisciplinary teams caring for matopoietic stem cell transplantation (HSCT),11 disclosing a HM patients in clinical decision making. fatality rate of 33%, 33%, 34%, and 33%, respectively. In most of these studies, risk factors for worse outcome METHODS comprised advanced age, more severe HM type, progressive A steering committee (SC) appointed by the ESMO and EHA disease status, and COVID-19 severity. Of note, treatment- boards prepared a series of questions to be voted upon at mediated immune dysfunction, caused by e.g. chemo- the consensus meeting. The multidisciplinary expert panel immunotherapy or Bruton’s tyrosine kinase (BTK) inhibition was compiled based on nominations from ESMO and EHA. is the main driver of the low rate of seroconversion post The SC consisted of 35 members with expertise across HMs, COVID-19, estimated at 69% in the whole HM population.12 coordinated by two members, Christian Buske and Fran- The dismal outcome of COVID-19 in HM and the emer- cesco Passamonti, each representing the ESMO and EHA, gence of new virus variants with higher infectivity rate13 respectively. In order to develop the clinical questions to be emphasize the need for early introduction of a vaccination addressed at the consensus meeting, the SC reviewed program in these patients. It has been convincingly shown, relevant clinical evidence and basic research in HM patient however, that anti-COVID-19 vaccines elicit an impaired management. Insights from the literature review were antibody response in patients with HM.14-17 A lower rate of supplemented with expert clinical opinion to develop six seroconversion (40%-89%) has been reported in lympho- working packages (WPs), each coordinated by one member proliferative disorders due to disease and/or drug-induced of the SC (outlined in Table 1) with draft consensus state- B-cell or plasma cell depletion and/or disruption of the B- ments included in the toolbox. The final member panel cell receptor signaling pathway.18-23 A longer time from (including the SC members) consisted of 35 experts their exposure can favor immune response in these condi- (including 2 individuals who did not participate in the voting tions.21,23-28 Myeloid neoplasms have been studied less: the of consensus recommendations). The following modified rate of post vaccine seroconversion seems higher (85%- Delphi process was used for preparation, consensus, and 90%) in MPNs and chronic myeloid leukemia (CML),26,29-32 reporting between 21 May 2021 and 30 June 2021. 2 https://doi.org/10.1016/j.esmoop.2022.100403 Volume 7 - Issue 2 - 2022 C. Buske et al. ESMO Open Table 1. Overview of working packages and main statements Working package Questions Statements COVID-19 diagnosis, treatment, and What are efficient strategies to STATEMENT 1: Patients, persons in their close relationship, and caregivers must apply mitigation strategies (Coordinator: prevent SARS-CoV-2 infection? common preventive strategies such as: hygiene measures, physical distancing, wearing M. von Liliefeld-Toal) facial masks. and staying, if possible, in single bedrooms. Efforts in the reorganization of hematology units with telehealth to reduce clinic visits, regular SARS-CoV-2 swab testing and vaccination of health care personnel, of persons in close relationship to patients and caregivers are to be favored. Are anti-COVID-19 vaccines STATEMENT 2: Vaccination is strongly recommended. Whenever possible, vaccination indicated in HM patients to should be proposed before initiation of treatment. If this is not possible, vaccines can prevent SARS-CoV-2 infection? be administered any time during disease course or any therapy in principle. In the case an urgent treatment is required, withholding the planned therapy for receiving vaccines is not justified. To note, immune response might be severely reduced in those receiving B-cell depleting agents. Are current available vaccines STATEMENT 3: The benefits of vaccination far outweigh the risks of vaccine-related safe in HMs? adverse events and given the greater severity of the disease and higher risk of death, HM patients are considered a high-priority subgroup for SARS-CoV-2 vaccination. Who should be tested for SARS- STATEMENT 4: Diagnostic testing is mandatory at presentation of any COVID-19 CoV-2 at what time? symptoms and after COVID-19 diagnosis until receiving two negative results, even after receiving vaccination against SARS-CoV-2. We recommend screening all asymptomatic patients for SARS-CoV-2 at admission for in-hospital stay, 2-3 days later, and then following local policy. Concerning outpatient clinic visits, we encourage developing local policies according to local risk and recommend testing in the case of high SARS- CoV-2 incidence in the community. What type of test should be STATEMENT 5: NAT (nucleic acid amplification technique) testing is preferred, usually used with which material? using RT-PCR as the most sensitive method. Material from the respiratory tract should be used, swabs are preferred but spit tests, throat gargles, sputum and nasopharyngeal aspirates are also under investigation. The evaluation of serum neutralizing antibodies for detecting immune response after exposure to SARS-CoV-2 is encouraged, when feasible. HM treatment in the COVID-19 With the aim to reduce hospital STATEMENT 6: A cancer care prioritization and treatment intensity approach has been pandemic (Coordinator: J. Gribben) visits and stay during the adapted for HM patients during the pandemic. HM patients, deemed appropriate for pandemic, how is it possible to treatment because of their high-risk disease, should be imaged as needed and as apply imaging techniques to closely as possible to pre-pandemic levels. Imaging in HM patients with low-risk efficiently stage and restage disease should be restricted to that level which is necessary to assess their clinical risk HM patients? status. Should fertility preservation STATEMENT 7: Fertility preservation facilities should be offered wherever possible, facilities be guaranteed during particularly in young patients before undergoing intensive chemotherapy. The decision the SARS-CoV-2 pandemic? must consider the availability and accessibility of the local facilities. Are there different indications/ STATEMENT 8: To lower the risk of febrile neutropenia, consider extending the thresholds for growth factor indication of granulocyte colony-stimulating factor (G-CSF) for patients with support (granulocyte-colony intermediate (10%-20%) and high risk for febrile neutropenia (>20%), and specifically stimulating factors or for elderly patients with comorbidities. Immunoglobulin replacement, administration erythropoietin stimulating of which should be carefully weighed against the risk of additional hospital visits, can agents) or immunoglobulin be used favorably by subcutaneous application. replacement during the SARS- CoV-2 pandemic? Should the prevention and STATEMENT 9: In HM patients with SARS-CoV-2 infection, there is an increased risk of management of thromboembolic events and associated complications such as lung vessel obstructive thromboembolic events be thrombo-inflammatory syndrome. Prophylaxis using low molecular weight heparin different in HM patient with (LMWH) is recommended for inpatients. SARS-CoV-2? When can a SARS-CoV-2 STATEMENT 10: There is no clear definition of the time point when HM patients can be infected HM patient be considered healed from COVID-19. The decision to rechallenge anticancer treatment in considered cured and be the absence of symptoms of active viral infection should be individualized. Doctors may rechallenged with anticancer consider the time elapsed since the beginning of SARS-CoV-2 infection, sequential treatments? negative PCR tests, the presence of neutralizing antibodies, the type and risk of HM, and the treatment to be administered. During the SARS-CoV-2 STATEMENT 11: Even in the SARS-CoV-2 pandemic, participation in appropriate clinical pandemic, has the risk/benefit trials should be pursued for HM patients. The risk/benefit balance for including an balance for including an individual patient in a clinical trial is determined by multiple factors such as the R0 individual patient in a clinical index and caseload of the pandemic, health care organization characteristics, and trial changed? resources, as well as the nature of the interventional study. Telemedicine or local testing should be encouraged in this setting. HM management in the COVID-19 When should we initiate STATEMENT 12: In indolent lymphomas, including CLL and WM, ‘watch and wait’ is the pandemic: lymphoma including CLL lymphoma treatment in the recommended strategy for asymptomatic patients with low tumor burden. When (Coordinator: L. Arcaini) COVID-19 pandemic? Indolent treatment is indicated according to consensus guidelines, treatment should be versus aggressive lymphoma administered. In unvaccinated patients, however, treatment deferral after anti-SARS- CoV-2 vaccination should be considered in the absence of an urgent treatment indication. In newly diagnosed or relapsing aggressive lymphoma, patients should be treated according to guidelines and a general delay of treatment initiation is not recommended. In unvaccinated patients, in the absence of urgent treatment indication, however, an individual treatment deferral after anti-SARS-CoV-2 vaccination (at least one injection) may be considered. Whenever possible, patients with Continued Volume 7 - Issue 2 - 2022 https://doi.org/10.1016/j.esmoop.2022.100403 3 ESMO Open C. Buske et al. Table 1. Continued Working package Questions Statements lymphoma should be vaccinated against SARS-CoV-2 before the initiation of therapy. In the absence of an urgent treatment indication, a congruous interval (up to 4 weeks) before an anti-CD20 antibody-containing regimen should be respected. Should we modify lymphoma STATEMENT 13: If treatment is necessary in indolent lymphoma, less treatment in the COVID-19 immunosuppressive therapies (e.g. therapies avoiding anti-CD20 antibodies in CLL and pandemic? In indolent anti-CD20 maintenance in follicular lymphoma) and treatments with less need for lymphoma/CLL/WM, first line, hospital stays, without compromising efficacy, are recommended. Vaccination before maintenance, relapse start of treatment is recommended. Should we modify lymphoma STATEMENT 14: For aggressive lymphoma in the curative setting patients should be treatment in the COVID-19 treated according to consensus guidelines without compromising efficacy of treatment. pandemic? In first-line If treatment options are equivalent, less immunosuppressive therapies and treatment aggressive lymphoma (DLBCL, with less need for hospital stays are recommended. MCL, PTCL) and HL? Should we modify lymphoma STATEMENT 15: In the curative setting patients with relapsed aggressive lymphoma treatment in the COVID-19 should be treated according to consensus guidelines without compromising efficacy of pandemic? In relapsed treatment. If treatment options are equivalent or patients are in a non-curative aggressive lymphoma (DLBCL, situation, less immunosuppressive treatments with less need for hospital stays are MCL, PTCL) and HL? Should recommended. Patients with refractory and/or relapsed DLBCL, PTCL, and HL who are autologous, allogeneic SCT or eligible to autologous, allogeneic SCT or CAR-T cell therapy should first receive salvage CAR-T cell therapy be regimens. HDT/ASCT or CAR-T cell therapy should be considered in eligible patients postponed in the pandemic? with DLBCL and MCL. Delaying (or omitting) consolidative autologous SCT in PTCL patients in CR following induction therapy may be considered, as its role is still controversial. How to treat lymphoma in the STATEMENT 16: All positive cases should be investigated with lung computed case of SARS-CoV-2 positive tomography scan. In indolent lymphomas, if possible, defer commencement of asymptomatic or treatment until nasopharyngeal swab negativity and resolution of clinical symptoms. If oligosymptomatic patients? All already on treatment the decision to continue or stop treatment should be based on histological types, at diagnosis, the nature of the treatment and the severity of COVID-19. or during therapy HM management in the When is it mandatory to STATEMENT 17: Treatment should not be delayed for newly diagnosed MM patients COVID-19 pandemic: MM initiate myeloma treatment with active disease, as well as in cases of myeloma medical emergencies. Although (Coordinator: M. Dimopoulos) during the COVID-19 patients with established CRAB criteria should start treatment as soon as possible, MM pandemic? patients presenting with one lesion or SLiM-only criteria may delay treatment only for a limited time period in cases of extreme COVID-19 dissemination in the community. Depending on the local incidence of COVID-19, patients with a solitary plasmacytoma as the sole indication for treatment may only receive local radiotherapy initially. Patients with a diagnosis of monoclonal gammopathy of undetermined significance or smoldering MM are typically in long-term monitoring of their disease status. How to treat myeloma in the STATEMENT 18: In cases of MM patients with a positive PCR test for SARS-CoV-2, but case of SARS-CoV-2-positive with no symptoms of COVID-19, a 14-day quarantine should be considered if myeloma- asymptomatic or related events allow the delay of treatment. Otherwise, treatment should be given oligosymptomatic patients? with very close monitoring of symptoms for early detection of COVID-19 progression. If the patient has symptomatic COVID-19, antimyeloma treatment should be delayed until total clinical recovery from COVID-19. Should first-line myeloma STATEMENT 19: The combination of bortezomib and dexamethasone with treatment be adapted in the lenalidomide (VRd) or thalidomide (VTD), as well as the combination of daratumumab COVID-19 pandemic for with VTD (DaraVTD) is the most preferred induction therapy for transplant eligible transplant eligible/ineligible patients with possible modifications for patients with sufficient response. Patients with patients? high-risk disease features may receive ASCT, which could be postponed in patients with standard-risk disease, depending on the epidemiology of COVID-19 in the community, but not more than 3 months, if possible. For transplant ineligible patients, the indicated regimens include VRd or daratumumab- based therapies (DaraRd or DaraVMP). In cases of high incidence of COVID-19 in the community, an all-oral regimen such as Rd could be implemented and the addition of bortezomib or daratumumab could be made later or upon insufficient response. In general, patient visits to the hospital should be minimized, by e.g. de-intensification of treatment in responding patients, if treatment outcome is not compromised. Should recommendations for STATEMENT 20: Patients with MM who are in the maintenance phase of their maintenance therapy be treatment should continue with their oral therapy and reduce visits to the clinic. changed in the COVID-19 Subcutaneous bortezomib administration for high-risk patients might be self- pandemic? administered at home, if feasible, to avoid omission or delay of treatment and to minimize visits to the hospital. Should treatment of relapsed STATEMENT 21: Patients with symptomatic relapse should not delay treatment. All oral myeloma be changed in the regimens with equivalent efficacy should be preferred over regimens necessitating COVID-19 pandemic? frequent hospital visits. Alternatively, less intensive dosing schedules of intravenous Transplant eligible/non-eligible and subcutaneous drugs should be implemented, such as weekly administration of proteasome inhibitors and rapid infusions of monoclonal antibodies. Salvage transplant can be avoided during the COVID-19 pandemic. Are cellular therapies such as STATEMENT 22: Patients with standard-risk MM may delay upfront ASCT in ASCT or CAR-T cells to be communities with high incidence of COVID-19, whereas those with high-risk MM may postponed in the pandemic? proceed. Patients eligible for a clinical trial with CAR-T cells without alternative treatment options can proceed as well. In this situation and in cases where ASCT or the CAR-T cell procedure cannot be postponed according to physician’s discretion, Continued 4 https://doi.org/10.1016/j.esmoop.2022.100403 Volume 7 - Issue 2 - 2022 C. Buske et al. ESMO Open Table 1. Continued Working package Questions Statements exclusion of COVID-19 by PCR for SARS-CoV-2 is deemed necessary, along with strict precautions to prevent SARS-CoV-2 transmission in the transplant department. HM management in the Covid-19 Should any modification to STATEMENT 23: A risk-adapted treatment strategy based on patient’s condition, pandemic: AML/MDS/ALL standard of care treatment of therapeutic goals, and individual risk by IPSS-R should be adopted also in the (Coordinator: G. Sanz) MDS during the COVID-19 pandemic. pandemic be implemented? Should any modification to STATEMENT 24: Intensive chemotherapy should be offered without delay for eligible standard of care treatment of patients both at diagnosis and relapse. Low-intensity therapies (i.e. hypomethylating AML be implemented during agent þ/- venetoclax) might be preferable for older (>65 years of age) and/or unfit the COVID-19 pandemic? patients. For consolidation, the use of intermediate-dose cytarabine and/or reducing the number of cycles could be considered. Treatment of acute promyelocytic leukemia should not be modified. Should any modification to STATEMENT 25: During the COVID-19 pandemic initial induction, intensive post- standard of care treatment of remission therapy and maintenance therapy of ALL should be given with as few ALL during the COVID-19 modifications as possible in children, adolescents, and young adults, as well as in adult pandemic be implemented? patients. All phases of therapy and second-line treatments for refractory/relapsed patients should be started without delay. For Phþ ALL a chemotherapy-free approach should be considered. Should standard of care STATEMENT 26: Decisions about administering AML-, ALL-, and MDS-directed therapy treatment be modified or in patients with asymptomatic or mild COVID-19 should consider the indication for stopped in a SARS-CoV-2- treatment, goals of care, treatment intensity, and patient’s history of tolerance to positive MDS, AML, blast phase treatment. Delaying treatment until at least 2 weeks after resolution of symptoms and of MPN/CML, ALL patient with SARS-CoV-2 PCR negativity is recommended whenever possible. asymptomatic or mild COVID- 19 disease? Should the standard of care STATEMENT 27: All AML, ALL, and MDS patients should interrupt any active treatment treatment be modified or of his/her hematological malignancy and receive the best available therapy for COVID- stopped in a SARS-CoV-2- 19 along with the best supportive care for HM. positive patient with AML, blast phase of MPN/CML, ALL, or MDS and severe COVID-19 disease? Should allogeneic STATEMENT 28: Allogeneic HSCT is a curative treatment approach for patients with hematopoietic cell MDS, AML, and ALL. If indicated, a deferral of the HSCT or modification of the planned transplantation for patients conditioning regimen is not justified but can be considered on a case-by-case basis. In with AML, blast phase of MPN/ case of COVID-19 hot spot regions and/or lack of intensive care unit beds, transferring CML, ALL, or MDS be the patient to other centers should be considered. postponed, or conditioning regimen modified during the pandemic? HM management in the COVID-19 How to treat MPN or CML in STATEMENT 29: In case of asymptomatic or mild/moderate COVID-19, newly diagnosed pandemic: MPN/CML case of asymptomatic or mild/ CML patients should initiate CML treatment without modifications; moreover, there is (Coordinator: D. Rea) moderate symptomatic COVID- no indication to interrupt or modify TKI therapy in previously diagnosed CML patients 19? on continuous drug treatment. Likewise, therapy for MPN should not be adjusted in this situation. How to treat MPN or CML in STATEMENT 30: Treatment initiation in newly diagnosed CML with severe/critical the case of COVID-19 requiring COVID-19 disease should be evaluated on a case-by-case basis, considering the urgency hospitalization (severe or very of remission induction. In case of previously diagnosed CML patients, there is no severe)? indication to systematically interrupt or modify TKI therapy. Attention should be paid to the impact of potential TKI/anti-COVID-19 drug-drug interactions. In MPNs, particular attention should be paid to patients receiving ruxolitinib. Otherwise, therapies such as anticoagulants or cytoreductive therapy may need to be adjusted depending upon the patient’s individual clinical scenario. Is there any indication to STATEMENT 31: The general approach to CML patients does not require major change the current approach to modifications in the pandemic, whereas monitoring and supportive care need careful SARS-CoV-2-negative CML planning to guarantee safe outpatient treatment of CML patients. Home delivery and patients during the COVID-19 telemedicine should be encouraged. pandemic? Is there any indication to STATEMENT 32: The general approach to MPN patients does not require modifications change the current approach to due to the COVID-19 pandemic, whereas monitoring and supportive care need careful MPN patients during the planning to guarantee safe treatment of MPN patients outside the hospital setting. COVID-19 pandemic? Home delivery and telemedicine should be encouraged. Is SCT to be postponed for STATEMENT 33: HSCT should not be postponed for MPN/CML patients with strong MPN/CML patients during the indication for HSCT, while measures should be taken to guarantee post-HSCT pandemic? treatment, monitoring, and care for patients who acquire SARS-CoV-2 after HSCT. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ASCT, autologous stem cell transplantation; CAR-T, chimeric antigen receptor T-cell; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CR, complete remission; CRAB, end-organ damage due to hypercalcemia, renal failure, anemia and bone lesions; DaraRd, dar- atumumab, lenalidomide, dexamethasone; DaraVMP, daratumumab, bortezomib, melphalan, prednisone; DLBCL, diffuse large B-cell lymphoma; HDT, high-dose therapy; HM, hematological malignancy; HSCT, hematopoietic stem cell transplantation; IPSS-R, revised International Prognostic Scoring System; MCL, mantle cell lymphoma; MDS, myelo- dysplastic syndromes; MPN, myeloproliferative neoplasm; Ph, Philadelphia chromosome; PTCL, peripheral T-cell lymphoma; Rd, lenalidomide, dexamethasone; SCT, stem cell transplantation; SLiM, sixty percent bone marrow plasma cells; involved:uninvolved serum free light chain ratio  100; >1 focal lesions on MRI studies; TKI, tyrosine-kinase inhibitor; WM, Waldenstrom’s macroglobulinemia. Volume 7 - Issue 2 - 2022 https://doi.org/10.1016/j.esmoop.2022.100403 5 ESMO Open C. Buske et al. Background information including the WPs along with the Currently, there are efficient vaccines for immunocompetent statements were sent to panelists for their structured individuals, licensed against COVID-19.44-46 Generally, feedback (agree, disagree, abstain, with comments). The SC vaccines work in patients with HMs with immune47 and incorporated all comments and suggestions, with discussion clinical responses48-50 and are currently generally recom- of all disagreements, resulting in a revised set of WP mended.51-53 By consequence, one can assume that vacci- statements that were then sent for a second anonymous nation against SARS-CoV-2 might be effective in HMs,54 vote to all panelists. Consensus was considered to be however, these immunocompromised patients have not reached if agreement was recorded by >75% of panelists. been included in the registration clinical trials. Reports on Lack of agreement on a statement would elicit revision and anti-SARS-CoV-2 vaccine efficacy in HMs disclosed a lower a third voting round, resulting in either consensus or final humoral immune response compared with that obtained in rejection of the statement. the healthy population.14-32 In addition, HM patients receiving B-cell-depleting therapy, anti-CD38 monoclonal antibodies, and JAK inhibitors are at higher risk of failing RESULTS: CLINICAL QUESTIONS AND STATEMENTS seroconversion after SARS-CoV-2 vaccines .14-32 Concerning HSCT, many patients will lose their immunity following WP1: COVID-19 diagnosis, treatment, and mitigation transplantation, but can generally begin to be vaccinated strategies around 3 months after the procedure. In consideration of the potential ineffectiveness of the immune system, HM patients What are efficient strategies to prevent SARS-CoV-2 should be tested for seroconversion after SARS-CoV-2 infection? vaccines and should maintain all the protective measures. There is no rationale to stop ongoing therapy prevaccination, STATEMENT 1: Patients, persons in their close relationship, since side-effects are not influenced by concurrent HM and caregivers must apply common preventive strategies treatment.55 such as: hygiene measures, physical distancing, wearing Final voting: agree 96.97%, disagree 3.03% (1/33). facial masks, and staying, if possible, in single bedrooms. Efforts in the reorganization of hematology units with Are current available vaccines safe in HMs? telehealth to reduce clinic visits, regular SARS-CoV-2 swab testing, and vaccination of health care personnel, of per- STATEMENT 3: The benefits of vaccination far outweigh sons in a close relationship to patients and caregivers are the risks of vaccine-related adverse events and given the to be favored. greater severity of the disease and higher risk of death, HM patients are considered a high priority subgroup for There are several studies indicating efficacy of preventing SARS-CoV-2 vaccination. strategies such as keeping distance, using face masks, and implementing quarantine and isolation in the control of SARS- Recent preliminary evidence in HMs showed that anti-SARS- CoV-2 transmission and thereby disease burden.33-39 Reorga- CoV-2 vaccines are safe.14-32,55,56 Rare cases of cerebral si- nization of clinic visits and management of hematology units to nus vein thrombosis or splanchnic vein thrombosis after reduce the risk of transmission have been reported by many to ChAdOx1 nCoV-19 and Ad26.COV2.S vaccination have been be feasible.40-42 Measures may include, but are not limited to reported in individuals between the ages of 20 and 55 implementing telehealth, defining dedicated areas and teams years.57-60 More recently, some cases of myocarditis after for care of HM patients and screening of the staff.This needs to COVID-19 messenger RNA vaccination have been described be adapted, however, to local strategies and policies. There is in younger cases.61 The benefits of vaccination far outweigh evidence to support the efficacy of vaccinating household vaccine-related risks, however, and vaccination is strongly members and caregivers derived from studies on vaccination recommended for patients with HMs. of staff in nursing homes.43 Final voting: agree 96.97%, abstain 3.03%, disagree 0% (0/ Final voting: agree 100%, disagree 0% (0/33). 33). Are anti COVID-19 vaccines indicated in HM patients to Who should be tested for SARS-CoV-2 at what time? prevent SARS-CoV-2 infection? STATEMENT 4: Diagnostic testing is mandatory at pre- STATEMENT 2: Vaccination is strongly recommended. sentation of any COVID-19 symptoms and after COVID-19 Whenever possible, vaccination should be proposed diagnosis until receiving two negative results, even after before initiation of treatment. If this is not possible, vac- receiving vaccination against SARS-CoV-2. We recommend cines can be administered any time during disease course screening all asymptomatic patients for SARS-CoV-2 at or any therapy in principle. In the case that an urgent admission for in-hospital stay, 2-3 days later, and then treatment is required, withholding the planned therapy following local policy. Concerning outpatient clinic visits, for receiving vaccines is not justified. To note, immune we encourage developing local policies according to local response might be severely reduced in those receiving risk and recommend testing in the case of high SARS-CoV-2 B-cell-depleting agents. incidence in the community. 6 https://doi.org/10.1016/j.esmoop.2022.100403 Volume 7 - Issue 2 - 2022 C. Buske et al. ESMO Open As there is clear evidence that patients with asymptomatic that the best results, however, can be expected from COVID-19 may spread the virus in any facility, screening of nasopharyngeal swabs or saliva.73-77 The evaluation of patients admitted for an in-hospital stay is the first and serum neutralizing antibodies for detecting immune foremost step to keep care facilities COVID-free areas.62 response after exposure to SARS-CoV-2 is encouraged, and Testing at presentation of symptoms should be carried in HM, a lower rate of seroconversion is expected as esti- out in all HM patients regardless of their current disease mated at 69%.12 status and therapy. Following several reports on prolonged Final voting: agree 90.91%, abstain 9.09%, disagree 0% viral shedding, especially in patients with severe course of (0/33). the disease and those with low numbers of B cells,63-65 it should be considered to carry out follow-up tests until negative results are confirmed before admission to the care WP2: HM treatment in the COVID-19 pandemic units. Viability of SARS-CoV-2 can only be proven by viral With the aim to reduce hospital visits and stay during the culture, but this is not routinely recommended. Therefore, pandemic, how is it possible to apply imaging techniques the interpretation of a positive detection should be care- to efficiently stage and restage HM patients? fully examined. Some institutions carry out screening in the outpatient clinic during phases of high incidence in their STATEMENT 6: A cancer care prioritization and treatment community. This is a feasible strategy to avoid spread intensity approach has been adapted for HM patients amongst those patients whose treatment cannot be de- during the pandemic. HM patients, deemed appropriate ferred. In the setting of acute leukemias, PCR testing before for treatment because of their high-risk disease, should be every chemotherapy cycle is strongly recommended. imaged as needed and as closely as possible to pre- Final voting: agree 93.94%, disagree 6.06% (2/33). pandemic levels. Imaging in HM patients with low-risk disease should be restricted to that level which is neces- What type of test should be used with which material? sary to assess their clinical risk status. STATEMENT 5: Nucleic acid amplification technique (NAT) For HMs in the curative setting, the risk-benefit balance testing is preferred, usually using RT-PCR as the most during the SARS-CoV-2 pandemic clearly favors maintaining sensitive method. Material from the respiratory tract established treatment guidelines, and multidisciplinary dis- should be used, swabs are preferred but spit tests, throat cussions should recommend standard imaging. In HM pa- gargles, sputum and naso-pharyngeal aspirates are also tients with low-risk disease, imaging should be restricted to under investigation. The evaluation of serum neutralizing that necessary to assess clinical risk status. To note, imaging antibodies for detecting immune response after exposure resources may be limited during the pandemic for moni- to SARS-CoV-2 is encouraged, when feasible. toring COVID-19 patients. Finally, a careful scheduling of imaging may avoid unnecessary hospital visits. The current gold standard and most widely used assays for Final voting: agree 100%, disagree 0% (0/33). the diagnosis of SARS-CoV-2 infection are based on RT-PCR and reported on the web at https://www.360dx.com/ Should fertility preservation facilities be guaranteed dur- coronavirus-test-tracker-launched-covid-19-tests. Target ing the SARS-CoV-2 pandemic? genes tested include RNA-dependent RNA polymerase (RdRp), open reading frame (ORF1), envelope (E), and STATEMENT 7: Fertility preservation facilities should be nucleocapsid (N) genes of the SARS-CoV-2 genome. False- offered wherever possible, particularly in young patients negative results may be due to improper sampling, degra- before undergoing intensive chemotherapy. The decision dation of the viral RNA during shipping/storage, low viral must consider the availability and accessibility of the local loads, incorrect nucleic acid extraction, presence of ampli- facilities. fication inhibitors, and mutations in the RT-PCR target re- gion. A false positive is mostly due to sample cross While hematologists should continue to discuss fertility contamination. To note, in long lasting positive tests,66 issue with patients to maximize the likelihood of a suc- viability of SARS-CoV-2 can only be proven by viral cul- cessful pregnancy after chemotherapy regimens, the pos- ture, however, this is not recommended routinely. NAT is sibility to offer fertility preservation during the pandemic preferred over antigen testing to diagnose SARS-CoV-2 may be compromised by limited facility availability. infection, because of higher sensitivity. In fact, the sensi- Depending on patients’ preferences, less intensive regimens tivity of antigen tests may drop down to 50% in asymp- [e.g. ABVD (Adriamycin, bleomycin, vinblastine, dacarba- tomatic cases, which does not make them a reliable tool for zine) instead of escalated BEACOPP (bleomycin, etoposide, the diagnosis of infection, especially in HMs.67-72 Most doxorubicin, cyclophosphamide, vincristine, procarbazine, centers use swabs for detecting SARS-CoV-2 RNA, but prednisone) for patients with Hodgkin’s lymphoma (HL)] alternative clinical samples, like saliva or sputum, may may be an option when semen or oocyte/ovarian tissue also provide reliable results and reduce contact between cryopreservation is not feasible. health care personnel and infected individuals. It seems Final voting: agree 90.91%, disagree 9.09% (3/33). Volume 7 - Issue 2 - 2022 https://doi.org/10.1016/j.esmoop.2022.100403 7 ESMO Open C. Buske et al. Are there different indications/thresholds for growth fac- Final voting: agree 93.94%, disagree 6.06% (2/33). tor support (granulocyte colony-stimulating factors or erythropoietin-stimulating agents) or immunoglobulin When can a SARS-CoV-2-infected HM patient be considered replacement during the SARS-CoV-2 pandemic? cured and be rechallenged with anticancer treatments? STATEMENT 8: To lower the risk of febrile neutropenia, STATEMENT 10: There is no clear definition of the time consider extending the indication of granulocyte colony- point when HM patients can be considered healed from stimulating factor (G-CSF) for patients with intermediate COVID-19. The decision to rechallenge anticancer treat- (10%-20%) and high risk for febrile neutropenia (>20%), ment in the absence of symptoms of active viral infection and specifically for elderly patients with comorbidities. should be individualized. Doctors may consider the time Immunoglobulin (Ig) replacement, administration of which elapsed since the beginning of SARS-CoV-2 infection, should be carefully weighed against the risk of additional sequential negative PCR tests, the presence of neutralizing hospital visits, can be used, favorably by SC application. antibodies, the type and risk of HM, and the treatment to be administered. Most systemic therapies used in high-risk HM are associated with a significant risk of immunosuppression. Therefore, Initially, two negative PCR tests more than 24 h apart were relevant supportive measures should be implemented such required to confirm cure of SARS-CoV-2 infection. To note, as prophylactic use of hematopoietic growth factors in all many HM patients have positive PCR tests for prolonged regimens with a medium/high risk of immunosuppression.78 periods without active infection.66 Studies on the associa- Moreover, to lower the risk of febrile neutropenia, the tions between swab test result, number of cycle thresholds, indication for G-CSF can be extended. The theoretical viral loads, viral cultures and disease status and infectivity, concern raised of acute respiratory failure due to G-CSF- however, did not include significant numbers of severely induced leukocyte recovery in patients with a pulmonary immunosuppressed patients or patients with HM82,83 and infection due to SARS-CoV-2 does not outweigh the benefit, therefore these data cannot be considered final. Viral but G-CSF should be applied with caution.79 The use of persistence, reactivation, or reinfection with novel variants erythropoietin, within guidelines indication, can be consid- of SARS-CoV-2 is a potential risk for the patients resuming ered to prevent patients’ visits for blood transfusion. After therapy, and for other HM patients in the same wards and careful review and confirmation of the indication, Ig should outpatient clinics. There are a number of reports of pro- be maintained where possible to avoid further infectious longed infections in immunosuppressed patients, especially complications. If available, subcutaneous formulations can if receiving corticosteroids, intensive treatments, and anti- be a useful alternative and avoid prolonged hospital stays CD20 monoclonal antibodies.84,85 The decision to rechal- and unnecessary visits. lenge with anticancer therapy should consider the type of Final voting: agree 96.97%, disagree 3.03% (1/33). treatment being proposed, since there is a suggestion that some targeted therapies are relatively safe even during Should the prevention and management of thromboem- SARS-CoV-2 infection,20-23 whereas immunochemotherapy bolic events be different in HM patients with SARS-CoV-2? poses bigger risks. Final voting: agree 93.94%, abstain 6.06%, disagree 0% (0/ STATEMENT 9: In HM patients with SARS-CoV-2 infection, 33). there is an increased risk of thromboembolic events and associated complications such as lung vessel obstructive During the SARS-CoV-2 pandemic, has the risk/benefit thrombo-inflammatory syndrome. For hospitalized patients, balance for including an individual patient in a clinical trial prophylaxis using low molecular weight heparin (LMWH) is changed? recommended for SARS-CoV-2-infected patients. STATEMENT 11: Even in the SARS-CoV-2 pandemic, There are a number of hemostatic alterations associated participation in appropriate clinical trials should be pur- with SARS-CoV-2.80,81 In HM patients, prophylaxis of sued for HM patients. The risk/benefit balance for thromboembolic events should be continued according to including an individual patient in a clinical trial is deter- existing guidelines. Patients should receive careful moni- mined, however, by multiple factors such as the R0 index toring as routinely as possible to prevent possible bleeding and caseload of the pandemic, health care organization complications. Patients hospitalized with a confirmed characteristics and resources, as well as the nature of the diagnosis of COVID-19 should receive prophylaxis of interventional study. Telemedicine or local testing should thromboembolic events using LMWH or fondaparinux, or be encouraged in this setting. even unfractionated heparin, if critically ill with a signifi- cantly reduced kidney function. When direct oral antico- In many instances, clinical trials represent the best possible agulants are used as prophylaxis, possible drug interactions chance of a successful outcome for HM patients. Trials with with medications that are tested for use against SARS-CoV-2 a high probability to need inpatient care, intensive care must be considered and reviewed by pharmacists. The role facilities, and in areas with high incidence of SARS-CoV-2 of full therapeutic anticoagulation in severely ill patients infection can be temporarily considered of lower priority with SARS-CoV-2 remains controversial. and deferred during the pandemic. Therefore, depending on 8 https://doi.org/10.1016/j.esmoop.2022.100403 Volume 7 - Issue 2 - 2022 C. Buske et al. ESMO Open the level of resources available for clinical trial activities, Should we modify lymphoma treatment in the COVID-19 doctors should prioritize interventional studies with the pandemic? In indolent lymphoma/CLL/WM, first line, following characteristics: (i) trials with drugs with expected maintenance, relapse high likelihood of benefit (e.g. very promising activity in early-phase or molecularly-selected therapy), (ii) trials with STATEMENT 13: If treatment is necessary in indolent experimental drugs supposed to be safer than the standard lymphoma, less immunosuppressive therapies [e.g. ther- of care, (iii) trials with low intensity treatment, and (iv) trials apies avoiding anti-CD20 antibodies in CLL and anti-CD20 in diseases or conditions without an effective standard of maintenance in follicular lymphoma (FL)] and treatments care. During the SARS-CoV-2 pandemic, deviations from with less need for hospital stays, without compromising clinical trial protocols have very often been unavoidable. efficacy are recommended. Vaccination before start of Treating physicians should remain as close as possible treatment is recommended. within the provisions of clinical trial protocols, however, so that the risk/benefit balance of the clinical trial remains In indolent lymphoma with limited disease, if treatment is acceptable. indicated, a radiotherapy approach is encouraged according Final voting: agree 93.94%, abstain 6.06%, disagree 0% (0/ to established guidelines. When treatment is necessary, the 33). type of therapy should be decided based on the most effective treatment and, only if with comparable efficacy, one should consider the less immunosuppressive alternative. WP3: HM management in the COVID-19 pandemic: Accordingly, if feasible, outpatient management with oral lymphoma including CLL drugs may be preferred, limiting the access and length of stay When should we initiate lymphoma treatment in the in hospital. For patients with advanced FL, monotherapy with COVID-19 pandemic? Indolent versus aggressive rituximab, rituximab þ lenalidomide (if available) or less lymphoma intensive immunochemotherapy, or R/O-CVP (rituximab/ obinutuzumab, cyclophosphamide, vincristine, prednisone) STATEMENT 12: In indolent lymphomas, including CLL and should be considered. In first line, immunosuppressive ap- Waldenstrom’s macroglobulinemia (WM), ‘watch and wait’ proaches (i.e. bendamustine) should be avoided if possible is the recommended strategy for asymptomatic patients and R/O-CVP or R/O-CHOP (combination chemotherapy with with low tumor burden. When treatment is indicated ac- cyclophosphamide, doxorubicin, vincristine and prednisone) cording to consensus guidelines, treatment should be are preferred over bendamustine-R/O because of their lower administered. In unvaccinated patients, however, treatment immunosuppressive potential. Fludarabine-based regimens deferral after anti-SARS-CoV-2 vaccination should be (fludarabine, cyclophosphamide, and rituximab) should be considered in the absence of an urgent treatment indication. avoided. The risk of immunosuppression related to maintenance In newly diagnosed or relapsing aggressive lymphoma, has to be considered and discussed with the individual patients should be treated according to guidelines and a patient. The decision to start or continue maintenance general delay of treatment initiation is not recommended. treatment with anti-CD20 may be considered according to In unvaccinated patients, however, in the absence of ur- the local epidemiological situation and vaccination status. gent treatment indication, an individual treatment In the relapsed/refractory setting, if feasible, outpatient deferral after anti-SARS-CoV-2 vaccination (at least one management with oral drugs should be considered with injection) may be considered. Whenever possible, patients limited access to the hospital and drugs including lenali- with lymphoma should be vaccinated against SARS-CoV-2 domide in FL patients should be considered. before the initiation of therapy. In the absence of an ur- In CLL, targeted oral therapies, especially BTK inhibitors gent treatment indication, a congruous interval (up to 4 or venetoclax, should be a preferred option over immu- weeks) before an anti-CD20 antibody-containing regimen nochemotherapy, if available, in both first line and re- should be respected. fractory/relapse setting, according to the approval of each drug. The use of anti-CD20 antibodies in association with Patients with lymphoma should be treated in highly novel inhibitors should be carefully evaluated and post- specialized hematology centers in which general principles poned if possible. have been implemented to minimize the risk of COVID-19 Final voting: agree 84.85%, abstain 9.09%, disagree 6.06% spreading, such as repeat testing. For indolent lymphoma/ (2/33). CLL/WM requiring therapy, more flexibility in the initiation of therapy may be frequently explored. If indolent lym- Should we modify lymphoma treatment in the COVID-19 phoma requires therapy according to national consensus pandemic? In first-line aggressive lymphoma (diffuse guidelines, however, then treatment should not be delayed. large B-cell lymphoma, mantle cell lymphoma, peripheral For aggressive lymphoma, delays in treatment initiation can T-cell lymphoma) and HL? result in significant worsening of the outcome. Final voting: agree 87.88%, abstain 12.12%, disagree 0% STATEMENT 14: For aggressive lymphoma in the curative (0/33). setting, patients should be treated according to consensus Volume 7 - Issue 2 - 2022 https://doi.org/10.1016/j.esmoop.2022.100403 9 ESMO Open C. Buske et al. guidelines without compromising efficacy of treatment. If remission following induction therapy may be considered, treatment options are equivalent, less immunosuppres- as its role is still controversial. sive therapies and treatment with less need for hospital stays are recommended. A high risk of death in patients undergoing intensive chemotherapy treatment which causes profound cytopenia Referral to COVID-free centers should be particularly consid- is expected. This includes treatments such as high-dose ered for patients with aggressive lymphomas. R-CHOP is a methotrexate, DHAP (cisplatin, cytarabine, dexametha- standard of care also during the COVID-19 pandemic, due to its sone), escalated BEACOPP, intensive autologous and allo- curative potential in diffuse large B-cell lymphoma (DLBCL). R- geneic HSCT. Despite this, in DLBCL, ASCT should be carried mini CHOP with G-CSF support can be considered for the out without delay if the procedure is considered. elderly; regimens different from R-CHOP [for instance dose- Final voting: agree 93.94%, abstain 6.06%, disagree 0% (0/ adjusted etoposide, prednisone, vincristine, cyclophospha- 33). mide, and doxorubicin plus rituximab (DA-EPOCH-R)] may be individually considered in specific situations (e.g. primary How to treat lymphoma in the case of SARS-CoV-2-positive mediastinal large B-cell lymphoma, double hit lymphoma). asymptomatic or oligosymptomatic patients? All histo- Addition of high-dose methotrexate and high-dose cytarabine logical types, at diagnosis, or during therapy and/or intrathecal methotrexate should have a clinical justification. STATEMENT 16: All positive cases should be investigated In patients with mantle cell lymphoma (MCL), high-dose with lung computed tomography (CT) scan. In indolent therapy with autologous stem cell transplantation (HDT/ lymphomas, if possible, defer commencement of treat- ASCT) as first-line consolidation may be delayed depending on ment until nasopharyngeal swab negativity and resolution the local epidemiological situation. Differently from FL, ritux- of clinical symptoms. If already on treatment the decision imab maintenance should be considered due to the demon- to continue or stop treatment should be based on the strated improved survival. Subcutaneous (s.c.) rituximab is nature of the treatment and the severity of COVID-19. recommended to reduce the time spent in the clinic. It is not recommended to delay therapy initiation for In all positive cases, a characterization of COVID-19 patients patients with peripheral T-cell lymphoma (PTCL) and HL. with a lung CT scan, SARS-CoV-2 PCR tests, and serology is Regarding PTCL, CHOP þ/- etoposide is indicated for most indicated. In indolent lymphomas, including CLL and WM, if patients with PTCL, even in the COVID-19 pandemic. Eto- possible, defer commencement of treatment until naso- poside may be omitted, however, in patients >60 years of pharyngeal swab negativity and resolution of clinical age due to increased risk of myelotoxicity and no advantage symptoms. If already on treatment and with mild symp- in PFS in comparison with CHOP alone in this age group. toms, BTK inhibitor therapy in WM might be continued, For patients with previously untreated high-grade ‘double given the risk of IgM rebound and constitutional symptoms hit’ or ‘triple hit’ B-cell lymphoma and primary mediastinal upon withdrawal.86,87 Therapy with other novel inhibitors B-cell lymphoma, immunochemotherapy with DA-EPOCH-R might be continued in the presence of a mild form of the remains a frontline option during the COVID-19 pandemic, disease not requiring hospitalization. Targeted therapies as R-CHOP may be suboptimal in this patient group. should be withheld, in case of hospitalization and/or need Final voting: agree 96.97%, disagree 3.03% (1/33). of oxygen therapy, until recovery. They could be resumed if patients are asymptomatic for at least 48 h and at least 14 Should we modify lymphoma treatment in the COVID-19 days after symptoms have started88 and, if possible, after pandemic? In relapsed aggressive lymphoma (DLBCL, two consecutive negative RT-PCR tests collected each MCL, PTCL) and HL? Should autologous, allogeneic SCT or approximately 1 week apart. Monoclonal antibodies and/or chimeric antigen receptor T-cell therapy be postponed in chemotherapy should be withheld until full characterization the pandemic? of the COVID-19 infection is carried out and until the pa- tient is asymptomatic for 48 h, at least 14 days after STATEMENT 15: In the curative setting, patients with symptoms start and, if possible, until nasopharyngeal swab relapsed aggressive lymphoma should be treated accord- negativity.88 If there is no immediate threat from lym- ing to consensus guidelines without compromising efficacy phoma, consider delaying chemotherapy until nasopharyn- of treatment. If treatment options are equivalent or pa- geal swab negativity. In aggressive lymphoma, when tients are in a non-curative situation, less immunosup- feasible, it is better to delay the start of treatment without pressive treatments with less need for hospital stays are compromising treatment in a curative setting. recommended. Patients with refractory and/or relapsed Final voting: agree 93.94%, abstain 6.06%, disagree 0% (0/ DLBCL, PTCL, and HL who are eligible to autologous, allo- 33). geneic SCT or chimeric antigen receptor T-cell (CAR-T cell) therapy should first receive salvage regimens. HDT/ASCT WP4: HM management in the COVID-19 pandemic: MM or CAR-T cell therapy should be considered in eligible patients with DLBCL and MCL. Delaying (or omitting) When is it mandatory to initiate myeloma treatment consolidative autologous SCT in PTCL patients in complete during the COVID-19 pandemic? 10 https://doi.org/10.1016/j.esmoop.2022.100403 Volume 7 - Issue 2 - 2022 C. Buske et al. ESMO Open STATEMENT 17: Treatment should not be delayed for time period.64,84,90,96 The management of MM in the era of newly diagnosed MM (NDMM) patients with active dis- COVID-19 is challenging.8,97 Asymptomatic patients for COVID- ease, as well as in cases of myeloma medical emergencies. 19 should stay quarantined at home for at least 14 days, under Although patients with presence of end-organ damage due close surveillance for detecting COVID-19-associated signs and to hypercalcemia, renal failure, anemia and bone lesions symptoms, in cases where antimyeloma therapy can be (CRAB criteria) should start treatment as soon as possible, delayed. In patients with acute renal failure or any myeloma- MM patients presenting with one lesion or SLiM-only related condition that requires medical attention, treatment criteria (Sixty percent bone marrow plasma cells; Invol- should be administered.90 If antimyeloma treatment has been ved:uninvolved serum free Light chain ratio ‡ 100; > 1 initiated, this might continue for patients with an asymptom- focal lesions on MRI studies) may delay treatment only for atic COVID-19 and active myeloma [MM-related symptoms, a limited time period in cases of extreme COVID-19 new diagnosis, recent relapse, suboptimal response to treat- dissemination in the community. Depending on the local ment, e.g. less than very good partial response (VGPR)] with incidence of COVID-19, patients with a solitary plasmacy- close monitoring of COVID-19-related symptoms. Steroids and toma as the sole indication for treatment may only receive drugs inducing lymphopenia could be de-intensified. Prophy- local radiotherapy initially. Patients with a diagnosis of lactic G-CSF for the prevention of neutropenia should be monoclonal gammopathy of undetermined significance considered. (MGUS) or smoldering MM (SMM) are typically in long- Upon the emergence of symptomatic infection, treatment term monitoring of their disease status. should be interrupted and the dose of steroids should be adjusted according to the treatment algorithm for COVID-19.98 Patients with NDMM with active disease should initiate Although symptomatic patients with mild COVID-19 may stay treatment.89 In the presence of SLiM criteria, treatment at home, close surveillance for aggravating symptoms is initiation might be delayed only for a limited time period in necessary.90 Upon such clinical suspicion, patient referral to a cases of high COVID-19 dissemination in the community. reference center for COVID-19 should not be delayed, because Treatment cannot be postponed in cases of myeloma the clinical presentation may deteriorate rapidly and early emergencies.90 Severe anemia, hypercalcemia, and renal intervention may be life-saving. For patients enrolled in a failure may necessitate hospitalization and immediate clinical trial, investigational agents should be interrupted until initiation of antimyeloma treatment, along with supportive COVID-19 resolution and the reporting should abide with the care.91 Spinal cord compression may necessitate immediate corresponding guidelines. initiation of radiotherapy and/or orthopedic decompensa- Final voting: agree 90.91%, abstain 9.09%, disagree 0% (0/ tion.92-94 Orthopedic treatment of impeding fractures and 33). radiotherapy for palliation of pain unresponsive to analge- sics should not be postponed.92,94 Patients with a diagnosis Should first-line myeloma treatment be adapted in the of MGUS or SMM do not require immediate treatment. COVID-19 pandemic for transplant eligible/ineligible Scheduled visits of patients with stable disease can be safely patients? delayed. Alternatively, blood examination in local labora- tories and consultation via telemedicine is encouraged. It STATEMENT 19: The combination of bortezomib and should be stressed that patients with high-risk disease dexamethasone with lenalidomide (VRd) or thalidomide should be carefully monitored for development of symp- (VTD), as well as the combination of daratumumab with tomatic disease requiring treatment.95 VTD (DaraVTD), is the most preferred induction therapy Final voting: agree 96.97%, abstain 3.03%, disagree 0% (0/33). for transplant eligible patients with possible modifications for patients with sufficient response. Patients with high- How to treat myeloma in the case of SARS-CoV-2-positive risk disease features may receive ASCT, which could be asymptomatic or oligosymptomatic patients? postponed in patients with standard-risk disease, depending on the epidemiology of COVID-19 in the com- STATEMENT 18: In cases of MM patients with a positive PCR munity, but not more than 3 months, if possible. test for SARS-CoV-2, but with no symptoms of COVID-19, a 14-day quarantine should be considered if myeloma-related For transplant ineligible patients the indicated regimens events allow the delay of treatment. Otherwise, treatment include VRd or daratumumab-based therapies [DaraRd should be given with very close monitoring of symptoms for (daratumumab, lenalidomide, dexamethasone) or Dar- early detection of COVID-19 progression. If the patient has aVMP (daratumumab, bortezomib, melphalan, predni- symptomatic COVID-19, antimyeloma treatment should be sone)]. In cases of high incidence of COVID-19 in the delayed until total clinical recovery from COVID-19. community, an all-oral regimen such as Rd could be imple- mented and the addition of bortezomib or daratumumab Patients with MM and COVID-19 should be treated as per could be made later or upon insufficient response. standard guidelines starting from isolation measures. The im- mune deregulation due to both myeloma- and treatment- In general, patient visits to the hospital should be mini- related factors may result in a prolonged viral shedding and, mized, by e.g. de-intensification of treatment in responding subsequently, positive PCR for SARS-CoV-2 for a prolonged patients, if treatment outcome is not compromised. Volume 7 - Issue 2 - 2022 https://doi.org/10.1016/j.esmoop.2022.100403 11 ESMO Open C. Buske et al. For transplant-eligible NDMM patients, induction treatment whereas disease monitoring and safety assessment can be can be administered for an extended period for up to six to easily carried out with telemedicine. Bortezomib injections eight cycles.90 The combination of bortezomib with lenali- for high-risk patients can be administered in extended time domide or thalidomide and dexamethasone (VRd or VTD), as periods, such as monthly instead of every 2 weeks, or delayed well as the combination of daratumumab with VTD (Dar- until the decrease in COVID-19 burden in the community. aVTD) represent the preferred induction therapy.99-102 The Final voting: agree 93.94%, abstain 6.06%, disagree 0% (0/ treatment schedule can be modified, for patients with suffi- 33). cient response. Patients with high-risk disease features may receive ASCT after six to eight induction cycles due to Should treatment of relapsed myeloma be changed in the otherwise increased probability of progression. In view of the COVID-19 pandemic? Transplant eligible/non-eligible novel triplet (or quadruplet) upfront combinations for NDMM patients, the necessity of upfront ASCT has been STATEMENT 21: Patients with symptomatic relapse should challenged.103 In this context and due to the anticipated not delay treatment. All oral regimens with equivalent immunosuppression following ASCT, it is recommended to efficacy should be preferred over regimens necessitating postpone mobilization, stem cell harvest, conditioning, and frequent hospital visits. Alternatively, less intensive dosing ASCT, mainly in patients with standard-risk disease. Physi- schedules of intravenous and s.c. drugs should be imple- cians may completely avoid ASCT in patients with marginal mented, such as weekly administration of proteasome fitness due to age or comorbidities. Stem cell harvest without inhibitors and rapid infusions of monoclonal antibodies. mobilization chemotherapy should be considered for pa- Salvage transplant can be avoided during the COVID-19 tients receiving daratumumab and or lenalidomide-based pandemic. induction in order to achieve a sufficient stem cell Depending on the COVID-19 circumstances in the commu- yield.104,105 In this case, G-CSF-only mobilization with the nity, watchful waiting may be considered for biochemical potential addition of plerixafor should be considered in order relapses, especially for patients with a slow and gradual to avoid the immunosuppressive effect of high-dose cyclo- increase in the paraprotein level. Patients with refractory phosphamide. In case of close contact with a person diag- disease, new onset of CRAB features, or those with a nosed with COVID-19, however, stem cell harvests and any biochemical relapse and a history of aggressive relapse with transplant procedures should not be carried out within at rapid deterioration of the clinical presentation, however, least 14, and preferably 21, days from the last contact. should receive next-line treatment without delay.90 In transplant ineligible NDMM patients, treatment should Regarding the selection of treatment regimen, orally be based on all-oral regimens, e.g. lenalidomide with administered agents (ixazomib, lenalidomide, pomalido- dexamethasone (Rd), especially for unfit patients, whereas mide, panobinostat) should be considered based on logis- the addition of bortezomib or daratumumab can be tics. Neutropenia due to lenalidomide or pomalidomide considered for patients with high-risk disease, or for those must be managed according to published recommenda- without sufficient response to Rd.90,102 For fit or tions.106 Alternative therapeutic approaches are recom- intermediate-fit myeloma patients, Rd can be considered as mended instead of salvage HSCT or an allogeneic transplant. a bridge for two to three cycles, in case the COVID-19 Should a patient with relapsed/refractory MM achieve pandemic is at a peak in the hospital; otherwise, the sufficient response (e.g. VGPR or better), modifications in approved VRd or daratumumab-based therapies (DaraRd or the treatment schedule are advisable (once weekly instead DaraVMP) should be considered. Dexamethasone should be of twice weekly bortezomib/carfilzomib, monthly dar- reduced to 20 mg weekly, whereas de-escalation (or even atumumab infusions). Substitution of bortezomib or carfil- interruption) should be considered for responding patients, zomib with ixazomib, in cases of VGPR or better, is not especially after the completion of nine cycles of treatment. recommended, as it is not supported by clinical studies. Final voting: agree 90.91%, abstain 9.09%, disagree 0% (0/ There are no data for isatuximab once monthly and thus in 33). cases of combination with pomalidomide and dexametha- Should recommendations for maintenance therapy be sone, in countries where the combination has been changed in the COVID-19 pandemic? approved, the schedule of isatuximab administration has to remain unchanged (i.e. every 2 weeks).107 Similarly, elotu- STATEMENT 20: Patients with MM who are in the main- zumab in combination with pomalidomide and dexameth- tenance phase of their treatment should continue with asone should be given according to protocol.108 Selinexor or their oral therapy and reduce visits to the clinic. S.C. belantamab mafodotin can be used in triple-class refractory bortezomib administration for high-risk patients might be patients.102,109,110 self-administered at home, if feasible, to avoid omission or Final voting: agree 84.85%, abstain 15.15%, disagree 0% delay of treatment and to minimize visits to the hospital. (0/33). All oral regimens used for the maintenance phase of treat- Are cellular therapies such as ASCT or CAR-T cells to be ment can be safely administered in myeloma patients, postponed in the pandemic? 12 https://doi.org/10.1016/j.esmoop.2022.100403 Volume 7 - Issue 2 - 2022 C. Buske et al. ESMO Open STATEMENT 22: Patients with standard-risk MM may delay life-threatening, with moderate cytopenias, and fit): a upfront ASCT in communities with a high incidence of short delay starting treatment could be considered COVID-19, whereas those with high-risk MM may proceed. depending on the local hospital and intensive care unit Patients eligible for a clinical trial with CAR-T cells without (ICU) availability; and (iii) low priority (patients with stable alternative treatment options can proceed as well. In this clinical conditions, for whom treatment is unlikely to situation and in cases where ASCT or the CAR-T cell pro- provide a significant benefit, relapsed/refractory without cedure cannot be postponed according to physician’s eligibility for salvage therapies, and/or with multiple discretion, exclusion of COVID-19 by PCR for SARS-CoV-2 is comorbidities): best supportive care is indicated. deemed necessary, along with strict precautions to pre- Final voting: agree 84.85%, abstain 12.12%, disagree 3.03% vent SARS-CoV-2 transmission in the transplant (1/33). department. Should any modification to standard of care treatment of Both SCT and CAR-T cell therapy should be offered to all acute myeloid leukemia be implemented during the MM patients with anticipated survival benefit. Strict pre- COVID-19 pandemic? cautions to prevent SARS-CoV-2 transmission in transplant centers should be taken along with exclusion of COVID-19 STATEMENT 24: Intensive chemotherapy should be offered infection by PCR in patients undergoing ASCT or CAR-T without delay for eligible patients both at diagnosis and cell therapy. relapse. Low-intensity therapies (i.e. HMA D/- venetoclax) Final voting: agree 87.88%, abstain 12.12%, disagree 0% might be preferable for older (>65 years of age) and/or (0/33). unfit patients. For consolidation, the use of intermediate- dose cytarabine and/or reducing the number of cycles could be considered. Treatment of acute promyelocytic WP5: HM management in the COVID-19 pandemic: AML/ leukemia (APL) should not be modified. MDS/acute lymphoblastic leukemia Acute myeloid leukemia (AML) is an emergency medical Should any modification to standard of care treatment of condition in most cases and treatment cannot be post- MDS during the COVID-19 pandemic be implemented? poned. Intensive chemotherapy is and should be the standard of care for fit patients with AML, even during STATEMENT 23: A risk-adapted treatment strategy the COVID-19 pandemic. Decreasing the number of cycles based on patient’s condition, therapeutic goals, and during post-remission therapy (intermediate dose cytar- individual risk by revised International Prognostic abine, 1.0-1.5 g/m2), especially in some prognostically Scoring System (IPSS-R) should be adopted also in the favorable instances (i.e. CBF AML or NPM1mut/FLT3 ITDneg pandemic. AML), can be considered to reduce the duration of neu- tropenia and hospitalization without affecting efficacy in Patients with lower-risk MDS (IPSS-R score <3.5) are selected cases. Potentially curable refractory/relapsed usually red blood cell transfusion-dependent and the pri- patients in whom intensive chemotherapy could serve as mary aim should be to minimize transfusions, decrease a bridge to HSCT should also be treated without delay. hospital visits, and avoid potential shortage of blood Only in SARS-CoV-2-infected patients without prolifera- products. The transfusion threshold should be based on tive disease or low transfusion requirements may treat- the patient’s clinical condition and reduced to a hemo- ment be postponed until the infection is resolved. globin <7 g/dl whenever possible. Therapies driven to Treatment of older or unfit patients, e.g. with HMAs or improve anemia (erythropoietic-stimulating agents, lena- low-dose cytarabine coupled with venetoclax, should be lidomide, and luspatercept) or thrombocytopenia (throm- started in most instances as it has been shown to induce bopoietin agonists) should be started or continued as high remission rates, can minimize transfusion re- planned. Transfusions and those therapies should be quirements, and reduce hospital stay. Low-risk APL ideally delivered and given at home, whenever possible. should be treated with all-trans retinoic acid (ATRA) and The start of immunosuppressive therapies should be arsenic trioxide (ATO), whereas in high-risk patients delayed but continued in those already responding to idarubicin should be added to ATRA þ/- ATO. treatment. For higher-risk MDS (IPSS-R score 3.5), doc- Final voting: agree 84.85%, abstain 15.15%, disagree 0% tors should distinguish three different situations: (i) high (0/33). priority (patients whose condition is life-threatening or clinically unstable and/or a planned treatment resulting in Should any modification to standard of care treatment of a significant clinical benefit): treatment with hypo- acute lymphoblastic leukemia during the COVID-19 methylating agents (HMAs) should be started without pandemic be implemented? delay. In those responding, HMAs should be continued as planned, but a short delay between cycles could be STATEMENT 25: During the COVID-19 pandemic initial in- considered after at least six cycles of treatment. Targeted duction, intensive post-remission therapy, and mainte- therapies and clinical trials should be taken into account; nance therapy of acute lymphoblastic leukemia (ALL) (ii) intermediate priority (patients whose condition is not should be given with as few modifications as possible in Volume 7 - Issue 2 - 2022 https://doi.org/10.1016/j.esmoop.2022.100403 13 ESMO Open C. Buske et al. children, adolescents and young adults (AYA), as well as in FLT3 inhibitors in AML). AML, ALL, or APL consolidation and adult patients. All phases of therapy and second-line maintenance therapies could be delayed. Thrombosis pro- treatments for refractory/relapsed patients should be phylaxis is recommended if asparaginase is to be used and started without delay. For Philadelphia chromosome (Ph)- asparaginase should be omitted if thrombotic events are positive ALL a chemotherapy-free approach should be present. A low-intensity therapy as a bridge to HSCT in considered. patients with a high risk of progression could be considered. Patients already under active treatment, especially if pro- In ALL, modifications of the treatment plan are likely to be longed myelosuppression is expected (i.e. chemotherapy, associated with poorer outcomes. Adults with additional risk conditioning regimen, first three HMA cycles), must be factors for fatal COVID-19 (i.e. diabetes, asthma or chronic admitted to a COVID-19 unit and closely monitored. obstructive pulmonary disorders, and obesity) should be Restarting treatment should be based on resolution of closely followed. Steroids are considered safe for COVID-19 COVID-19 disease, especially if COVID-19 IgG antibodies are management and crucial for ALL, hence, they should be present. used without dose modification in all instances. In Ph- Final voting: agree 87.88%, abstain 12.12%, disagree 0% negative ALL, the general recommendation is to deliver ALL (0/33). therapy without modifications. For adult patients with Ph- positive ALL, especially if a high COVID-19 incidence and Should the standard of care treatment be modified or hospital occupancy are present, a tyrosine-kinase inhibitor stopped in a SARS-CoV-2-positive patient with AML, blast (TKI) with steroids is favored over intensive multidrug in- phase of MPN/CML, ALL, or MDS and severe COVID-19 duction chemotherapy for initial treatment. In sharp disease? contrast, intensive multidrug induction chemotherapy is recommended for children and AYA ALL patients. Aggressive STATEMENT 27: All AML, ALL, and MDS patients should post-remission therapy should be administered as scheduled, interrupt any active treatment of his/her HM and receive but the use of rituximab for consolidation is controversial the best available therapy for COVID-19 along with the due to the frequent need of hospital visits that could put best supportive care for HM. patients at risk. Patients with relapsed or resistant ALL The risk of death due to COVID-19 in these patients is very should be treated on a case-by-case basis and considering high. Any treatment driven to cure/avoid progression of the availability of clinical trials. Final voting: agree 93.94%, abstain 6.06%, disagree 0% (0/ their HM could substantially increase this risk and should be avoided until resolution of COVID-19. Patients must be 33). treated in a COVID-19 unit according to institutional policy. Should standard of care treatment be modified or stopped As with other patients with severe COVID-19 disease, in an SARS-CoV-2-positive MDS, AML, blast phase of MPN/ admission to ICU should be favored and based on their CML, ALL patient with asymptomatic or mild COVID-19 individual prognosis and expectancy of life. disease? Final voting: agree 87.88%, abstain 12.12%, disagree 0% (0/33). STATEMENT 26: Decisions about administering AML-, ALL-, and MDS-directed therapy in patients with Should allogeneic hematopoietic cell transplantation for asymptomatic or mild COVID-19 should consider the patients with AML, blast phase of MPN/CML, ALL, or MDS indication for treatment, goals of care, treatment in- be postponed, or conditioning regimen modified during tensity, and patient’s history of tolerance to treatment. the pandemic? Delaying treatment until at least 2 weeks after resolu- tion of symptoms and SARS-CoV-2 PCR negativity is STATEMENT 28: Allogeneic HSCT is a curative treat- recommended whenever possible. ment approach for patients with MDS, AML, and ALL. If indicated, a deferral of the HSCT or modification of Delaying treatment until COVID-19 symptoms have resolved the planned conditioning regimen is not justified but is recommended whenever possible and should be made on can be considered on a case-by-case basis. In case of a case-by-case basis, also considering treatment intensity. COVID-19 hot spot regions and/or lack of ICU beds, Lower-risk MDS patients responding to erythropoiesis- transferring the patient to other centers should be stimulating agents, luspatercept or lenalidomide, as well considered. as higher-risk MDS patients responding to HMAs beyond the third cycle without hematological toxicity should Patients with COVID-19 after HSCT have a severe course and continue their therapy as planned, especially if treatment a higher risk of mortality. In contrast, any delay in post- can be delivered at home. Treatment of the remaining MDS poning HSCT exposes patients to a high probability of patients should be postponed. Intensive chemotherapy in relapse. A perceived higher risk due to the COVID-19 AML or ALL should be delayed. In newly diagnosed patients pandemic does not justify a reduction of the conditioning with AML or ALL, low-intensity therapies to avoid progres- intensity. sion could be used (i.e. prednisone plus central nervous Final voting: agree 90.91%, abstain 9.09%, disagree 0% (0/ system prophylaxis in ALL and hydroxyurea and/or HMAs or 33). 14 https://doi.org/10.1016/j.esmoop.2022.100403 Volume 7 - Issue 2 - 2022 C. Buske et al. ESMO Open WP6: HM management in the COVID-19 pandemic: MPN/ planning to guarantee safe outpatient treatment of CML CML patients. Home delivery and telemedicine should be encouraged. How to treat MPN or CML in case of asymptomatic or mild/moderate symptomatic COVID-19? Treatment in newly diagnosed CML should not be postponed as remission induction is considered beneficial, even in the STATEMENT 29: In case of asymptomatic or mild/moder- pandemic. Caution is advised during the first 3 months of TKI ate COVID-19, newly diagnosed CML patients should treatment, however, as severe cytopenia may occur, thus initiate CML treatment without modifications; moreover possibly increasing the severity of COVID-19. The pandemic there is no indication to interrupt or modify TKI therapy in should not affect the choice of TKI. A recent study found an previously diagnosed CML patients on continuous drug increased mortality risk in CML patients with COVID-19 when treatment. Likewise, therapy for MPN should not be treated with imatinib, but this may be confounded by older adjusted in this situation. age, and access to and quality of health services.112 Patients already on treatment with TKIs should continue their treat- Therapies used to treat MPN/CML are not expected to in- ment. In case of pulmonary side-effects of TKIs, SARS-CoV-2 crease the risk of evolution to severe/very severe COVID-19 infection should be ruled out, and side-effects aggressively and treatment interruption may expose patients to loss of managed. A switch to another TKI may be considered. In response, or in the case of ruxolitinib, worsening of in- patients with long-lasting molecular remission (MR) 4 or flammatory symptoms.111 better, TKI may be stopped according to current guidelines Final voting: agree 93.94%, abstain 6.06%, disagree 0% (0/ and patients may be molecularly monitored monthly for the 33). first 6 months. During the pandemic, monitoring frequency and in-person visits should not be modified. In patients How to treat MPN or CML in the case of COVID-19 progressing to blast crisis, the indication for treatment should requiring hospitalization (severe or very severe)? not be modified or postponed. Finally, in women with CML STATEMENT 30: Treatment initiation in newly diagnosed who plan to become pregnant and in pregnant women with CML with severe/critical COVID-19 disease should be eval- CML, interferon treatment does not require adaptation due uated on a case-by-case basis, considering the urgency of to the COVID-19 pandemic. remission induction. In case of previously diagnosed CML Final voting: agree 96.97%, abstain 3.03%, disagree 0% (0/ patients, there is no indication to systematically interrupt or 33). modify TKI therapy. Attention should be paid to the impact of potential TKI/anti-COVID-19 drug-drug interactions. In Is there any indication to change the current approach to MPNs, particular attention should be paid to patients MPN patients during the COVID-19 pandemic? receiving ruxolitinib. Otherwise, therapies such as antico- STATEMENT 32: The general approach to MPN patients agulants or cytoreductive therapy may need to be adjusted does not require modifications due to the COVID-19 depending upon the patient’s individual clinical scenario. pandemic, whereas monitoring and supportive care need In CML, the decision to interrupt TKI treatment in case of careful planning to guarantee safe treatment of MPN pa- admission due to COVID-19 needs to be made on a case-to- tients outside the hospital setting. Home delivery and case basis considering time on TKI, response to TKI, type of telemedicine should be encouraged. TKI, and risk of CML relapse. To note, TKIs are not consid- Many patients with MPNs under ongoing treatment have ered immunosuppressive, and it is expected that almost all stable disease and can be supported with remote monitoring; patients still respond after a TKI discontinuation. In patients with concomitant TKI-related organ damage such as car- in some countries this care is already provided under guide- lines by specialist nurses, pharmacists, or family doctors. Some diovascular or pulmonary toxicity, the TKI should be patients, e.g. those with advanced phase or aggressive stopped until both COVID-19 and adverse events are myelofibrosis and transfusion dependence, require closer resolved. For MPN patients with COVID-19, ruxolitinib monitoring mostly in a hospital setting. For selected MPN discontinuation could be harmful.111 patients with stable disease, intensity of monitoring could Final voting: agree 90.91%, abstain 9.09%, disagree 0% (0/ likely be reduced for a limited time provided the patient has 33). good links to their routine team. For patients initiating or Is there any indication to change the current approach to changing therapy, the individual decision should be based on SARS-CoV-2 negative CML patients during the COVID-19 the advantage of initiating an effective treatment, the fre- pandemic? quency of monitoring during the first months of therapy, and the risk of COVID-19. In polycythemia vera (PV) and essential STATEMENT 31: The general approach to CML patients thrombocythemia (ET), delaying treatment initiation can in- does not require major modifications in the pandemic, crease the risk of thrombosis. In myelofibrosis, initiation of whereas monitoring and supportive care need careful ruxolitinib requires specific considerations. For those patients Volume 7 - Issue 2 - 2022 https://doi.org/10.1016/j.esmoop.2022.100403 15 ESMO Open C. Buske et al. already taking ruxolitinib, stopping the drug whilst having DISCLOSURE COVID-19 seems to be harmful. Overall, there is no indication CB reports honoraria from Roche/Genentech, Janssen, to modify current MPN guidelines even in the pandemic. BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead Sciences, Final voting: agree 96.97%, abstain 3.03%, disagree 0% (0/ Celltrion, MorphoSys, Regeneron; he reports consulting or 33). advisory role: Gilead Sciences, Janssen, Roche, Pfizer, Bei- Gene, Celltrion, AbbVie, Incyte, Regeneron, MorphoSys, Is SCT to be postponed for MPN/CML patients during the Novartis; he reports speaker’s engagement: Roche, Janssen, pandemic? BeiGene, Celltrion, AbbVie, Pfizer, Gilead Sciences; he re- STATEMENT 33: HSCT should not be postponed for MPN/ ports research funding: Roche/Genentech, Janssen, Cellt- CML patients with strong indication for HSCT, while mea- rion, Merck Sharp & Dohme (MSD), Pfizer, Amgen. sures should be taken to guarantee post-HSCT treatment, MD reports honoraria as Advisory Board Member of monitoring, and care for patients who acquire SARS-CoV-2 AstraZeneca, Bayer, BeiGene, Celgene, Genmab, Gilead, after HSCT. Incyte, Janssen, Lilly, MorphoSys, Novartis, Roche; he re- ports honoraria for speaker’s engagement from Amgen, SARS-CoV-2-negative patients with MPN/CML can receive AstraZeneca, Bayer, Celgene, Gilead, Janssen, Novartis, HSCT as indicated. In the case of SARS-CoV-2-positive pa- Roche; he reports institutional research grants from AbbVie, tients with high-risk MPN/CML, HSCT should be deferred Bayer, Gilead, Celgene, Janssen, Roche. until the patient is asymptomatic and has two negative PCR AA-L has declared no conflicts of interest. swabs taken at least 24 h apart. In patients with low-risk JA reports personal financial interests as advisory board disease, who were asymptomatic or only mildly symptom- and invited speaker from Incyte, advisory board from Mal- atic with upper respiratory tract symptoms, a deferral of at linckrodt, advisory board and invited speaker from Novartis, least 14 days after the first negative PCR test is indicated, advisory board and invited speaker from Pfizer; she reports with a new PCR test recommended before conditioning; for non-financial interests as principal investigator from Incyte, those with moderate to severe COVID-19, it is recom- principal investigator from Novartis. mended to defer HSCT for at least 3 months. LA received advisory honoraria from Roche, Celgene, Final voting: agree 96.97%, abstain 3.03%, disagree 0% (0/ Janssen-Cilag, Verastem, Eusa Pharma, Incyte, ADC Thera- 33). peutics and Gilead; research support from Gilead, and travel expenses from Roche, Celgene, Janssen-Cilag, and Eusa Pharma; speakers bureau from Novartis. Conclusions CB has declared no conflicts of interest. Using a structured method and relying on a panel of ex- LB reports Advisory Committee activities for AbbVie, perts, we have developed a detailed set of clinical state- Amgen, Astellas, Bristol Myers Squibb (BMS), Celgene, ments to guide health care professionals and assist them in Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, overcoming many of the clinical issues in HM management Menarini, Novartis, Pfizer, Sanofi, Seattle Genetics and has during the COVID-19 pandemic. The % rate of ‘abstain’ seen research support from Bayer and Jazz Pharmaceuticals. in some statements is due to the fact that several sub- PC has declared no conflicts of interest. specialized working groups produced statements that were MGDP has declared no conflicts of interest. subsequently voted upon in a plenary session by all co- MD reports personal fees from Amgen, personal fees authors, among whom some felt were outside their ‘core from Takeda, personal fees from Janssen, personal fees expertise area’. from BeiGene, personal fees from BMS, outside the sub- This set of recommendations reflects the knowledge at mitted work. the time point of writing. This implies that based on the SD reports personal financial interests as advisory board, high dynamics of the COVID-19 pandemic, the rapid in- invited speaker, fellow funding, and coordinating PI from crease in our understanding of COVID-19 biology, and the BeiGene, writing engagement from Karger, advisory board fast changes in the vaccination status of the general pop- and coordinating PI from Sanofi, funding, and other from ulation, this expert consensus should be considered as a Janssen; she reports non-financial interests as advisory role dynamic repository of clinical recommendations. at British Society for Haematology Lymphoma Special In- terest Group, advisory role at Lymphoma Action, member of ACKNOWLEDGEMENTS board of directors at WMUK Charity. The panel would like to acknowledge the work of Klizia HTE has declared no conflicts of interest. Marinoni and Delanie Young, from the Scientific and Med- RF reports honoraria for advisory boards and/or speaker ical Division at ESMO, for the project coordination and bureau from Janssen, Gilead, AbbVie, Amgen, Novartis, editorial assistance. Roche, Incyte, Pfizer, all outside the submitted work. PG reports grants and personal fees from AbbVie, grants and personal fees from Acerta/AstraZeneca, personal fees FUNDING from BeiGene, personal fees from Celgene/Juno/BMS, None declared. grants and personal fees from Janssen, personal fees 16 https://doi.org/10.1016/j.esmoop.2022.100403 Volume 7 - Issue 2 - 2022 C. Buske et al. ESMO Open from Lilly/Loxo, personal fees from MEI, personal fees from Novartis; membership on advisory boards: Incyte, Novartis Roche, personal fees from Sanofi, personal fees from Pharma, Pfizer. ArQule/MSD, outside the submitted work; J-MR reports grants and honoraria from Novartis, Amgen, MGdS reports grants, personal fees, non-financial sup- Pfizer, Takeda, Incyte, and Servier. port and other from Gilead Sciences, grants from AstraZe- TR has declared no conflicts of interest. neca, personal fees, non-financial support, and other from JF-M reports consulting and advisory boards honoraria Janssen Cilag, personal fees and non-financial support from (received by CUN ) from AbbVie, Amgen, BMS, Celgene, Roche, non-financial support from AbbVie, personal fees Janssen, GlaxoSmithKline, Karyopharm, MSD, Novartis, and non-financial support from BMS, personal fees and Takeda, Sanofi, SecuraBio, Regeneron, Roche, outside the non-financial support from MSD, personal fees and non- submitted work. financial support from Takeda, personal fees from Novar- VS has declared no conflicts of interest. tis, personal fees from ADC Therapeutics, outside the GFS reports personal fees and other from AbbVie, other submitted work. from Amgen, other from Astellas, other from Boehringer- JG reports personal fees from AbbVie, grants and per- Ingelheim, grants, personal fees and other from Celgene, sonal fees from AstraZeneca, grants and personal fees from other from Helsinn Healthcare, grants, personal fees, and other BMS/Celgene, grants and personal fees from Janssen, per- from Janssen-Cilag, grants and other from Novartis, other from sonal fees from Kite/Gilead, personal fees from MorphoSys, Onconova, grants, personal fees and other from Roche, and personal fees from Novartis, personal fees from TG Thera- other from Takeda, outside the submitted work. peutics, outside the submitted work. PS reports honoraria from Amgen, Celgene, Janssen, RH has had a consultant or advisory relationship with Karyopharm, SkylineDx, Takeda, and research support from Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, Pharma- Celgene, Janssen, Amgen, Takeda, BMS, SkylineDx, Kar- Mar, and Takeda; has received honoraria from Janssen, yopharm, all outside the submitted work. Amgen, Celgene, BMS, PharmaMar, and Takeda; has MvL-T has received travel grants and honoraria from received research funding from Janssen, Amgen, Celgene, Celgene, Gilead, Chugai, Janssen, Novartis, Amgen, Takeda, BMS, Novartis, and Takeda. BMS, Medac, Oncopeptides, Merck, CDDF, Pfizer, Medac, CH reports grants and personal fees from Novartis, grants Thermo Fisher, AstraZeneca; is a consultant for Celgene, and personal fees from BMS, personal fees from Sierra Gilead, Oncopeptides, MSD, 4D Pharma, Janssen, Shionogi Oncology, personal fees from CTI pharmaceuticals, personal and received research funding from BMBF, Deutsche Jose fees from Jannsen, personal fees from Geron, grants and Carreras Leukämie-Stiftung, IZKF Jena, Novartis, Gilead, personal fees from AOP Orphan Pharma, personal fees from Deutsche Krebshilfe, Celgene, Oncopeptides, Deutsche Galecto, grants, personal fees and other from Constellation, Forschungsgemeinschaft (DFG). outside the submitted work. CW has declared no conflicts of interest. MH reports personal fees from Novartis, personal fees GP reports grants from Amgen, grants, personal fees and from Pfizer, personal fees from Roche, personal fees from non-financial support from Merck, grants and non-financial AbbVie, personal fees from Daiichi Sankyo, personal fees support from AstraZeneca, grants and personal fees from from Bayer Pharma AG, personal fees from Jazz Pharma- Roche, grants and personal fees from BMS, grants from Lilly, ceuticals, personal fees from BMS, personal fees from Tol- grants and personal fees from MSD, grants and personal remo, outside the submitted work. fees from Novartis, outside the submitted work. BK has received honoraria for lectures from Ipsen, FP reports grants from Novartis, Celgene, BMS, Abbvie, Novartis and MSD (all outside of the submitted work). Karyopharma, Janssen. 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