Case report: High-risk acute promyelocytic leukemia and COVID-19-related myocarditis one patient, two cytokine storms.

Acute promyelocytic leukemia (APL) is a unique, highly curable subtype of acute myeloid leukemia, owing to the therapeutic advances of the last decades which led to high complete remission rates and excellent long-term survival. Nevertheless, it remains associated with high early mortality rates. Early death is the major cause of treatment failure in APL and is mainly attributed to coagulopathy, differentiation syndrome, and less commonly, infectious events. Timely recognition of each complication plays a crucial role in the management of patients diagnosed with APL. Coronavirus Infectious Disease 2019 (COVID-19) has shown great heterogeneity in patient presentation. Clinical manifestations range from asymptomatic disease to severe forms, mainly characterized by a hyperinflammatory syndrome leading to acute respiratory distress and multiorgan failure. Patients with acute leukemia and concomitant COVID-19-related hyperinflammatory syndrome have particularly poor outcomes. We hereby report the case of a 28-year-old male patient who was diagnosed with high-risk APL, with severe associated coagulopathy at presentation. He was treated with chemotherapy according to the AIDA regimen. The first week of induction therapy was complicated by a differentiation syndrome manifesting as fever not attributable to infection and respiratory distress with pulmonary infiltrates, resolved after ATRA discontinuation and corticotherapy. On the fourth week of treatment, he tested positive for acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with minor pulmonary involvement. Clinical manifestations over the following days included tachycardia and hypotension, associated with elevated inflammatory markers and cardiac biomarkers (troponin I x58 upper NV). Cardiovascular magnetic resonance imaging was consistent with myocarditis. COVID-19-associated myocarditis was successfully treated with methylprednisolone, intravenous immunoglobulins and Anakinra. Differentiation syndrome and COVID-19-associated myocarditis are two life-threatening complications that adversely impact survival. However, early recognition and prompt treatment initiation can improve clinical outcomes, as was the case of our patient.

A case report and literature review of management of high-risk newly diagnosed acute promyelocytic leukemia and co-existing COVID-19

Introduction Management of newly diagnosed acute myeloid leukemia (AML) together with severe coronavirus disease 2019 (COVID-19) is challenging;moreover, the optimal treatment is unknown. Patients with leukemia might be at a higher risk of developing COVID-19 because of associated myelosuppression in the case of AML. The authors present the management of a confirmed case of severe COVID-19 in a newly diagnosed patients with acute promyelocytic leukemia (APL) and review of the literature. Case A 33-year-old man got referred to the hematology outpatient clinic because of marked leukocytosis and moderate thrombocytopenia. He was diagnosed as having COVID-19 pneumonia and high-risk APL at the same time. AIDA protocol and COVID-19 pneumonia treatments had to be given at the same time. At the end of this successful treatment process, the patient was discharged with complete remission. Discussion APL is a distinct and rare type of AML. Coagulopathy is the most important cause of early death owing to APL. Although there is no consensus regarding the treatment approach to be applied in the co-existence of AML and COVID-19 infection, there are various recommendations. Conclusion The simultaneous diagnosis of high-risk APL and covid-19 is a challenging process for both patients and clinicians. (C) 2022 The Egyptian Journal of Haematology

Anti-SARS-CoV2 antibody-mediated cytokine release syndrome in a patient with acute promyelocytic leukemia.

BACKGROUND: Passive immunization against SARS-CoV-2 limits viral burden and death from COVID-19; however, it poses a theoretical risk of disease exacerbation through antibody-dependent enhancement (ADE). ADE after anti-SARS-CoV2 antibody treatment has not been reported, and therefore the potential risk and promoting factors remain unknown. CASE PRESENTATION: A 75-year-old female was admitted to the emergency room with recurrent, unexplained bruises and leukocytopenia, anemia, and thrombocytopenia. Evaluation of a bone marrow biopsy established the diagnosis of an acute promyelocytic leukemia (APL). SARS-CoV-2 RT-PCR testing of nasal and throat swabs on admission was negative. During the routine SARS-CoV-2 testing of inpatients, our patient tested positive for SARS-CoV-2 on day 14 after admission without typical COVID-19 symptoms. Due to disease- and therapy-related immunosuppression and advanced age conferring a high risk of progressing to severe COVID-19, casirivimab and imdevimab were administered as a preemptive approach. The patient developed immune activation and cytokine release syndrome (CRS) occurring within four hours of preemptive anti-SARS-CoV2 antibody (casirivimab/imdevimab) infusion. Immune activation and CRS were evidenced by a rapid increase in serum cytokines (IL-6, TNFα, IL-8, IL-10), acute respiratory insufficiency, and progressive acute respiratory distress syndrome. DISCUSSION AND CONCLUSION: The temporal relationship between therapeutic antibody administration and the rapid laboratory, radiological, and clinical deterioration suggests that CRS was an antibody-related adverse event, potentially exacerbated by APL treatment-mediated differentiation of leukemic blasts and promyelocytes. This case highlights the need for careful assessment of life-threatening adverse events after passive SARS-CoV-2 immunization, especially in the clinical context of patients with complex immune and hematological landscapes.

CLINICAL PROFILE AND THE OUTCOME OF COVID-19 IN PATIENTS WITH HEMATOLOGICAL MALIGNANCY: A SINGLE CENTRE EXPERIENCE

Objective: In the present study, we are reporting the clinical profile;and outcomes of COVID-19 in patients with hematological malignancy at tertiary care hospitals. Methods: Data from laboratory-confirmed 40 COVID-19 patients diagnosed between January 1, 2021 and July 31, 2021, were analyzed retrospectively. All COVID-19 patients with hematological malignancy (n=40) were included in the study. Results: In the present study, a total of 40 patients were included. Of 40, 25 (62.5%) were males, and 15 (37.5%) were females. The median age in this study was 43 years (Range, 8–70). Of these 40 patients, acute myeloid leukemia was the most common malignancy 11 (27.5%), followed by acute lymphoblastic leukemia 9 (22.5%) than non-Hodgkin lymphoma 5 (12.5%), plasma cell dyscrasia 4 (10%), chronic myeloid leukemia 4 (10%), chronic lymphocytic leukemia 3 (7.5%), acute promyelocytic leukemia 2 (5%), chronic myelomonocytic leukemia 2 (5%). Mean hemoglobin was (8.04 g/dl), white blood cell count was (10.14×109/l), platelet count was (77.7×109/l) creatinine was (0.86 mg/dl), bilirubin was (1.24 mg/dl). The overall case-fatality rate was 8 (22.5%). Conclusion: Patients with hematological malignancy are immunocompromised, and our study reveals that there is an increased case fatality rate among these patients. Hence, physicians should be aggressive in the management of COVID-19 patients with hematological malignancy.

Vancomycin Induced Maturation Arrest with Reactive Promyelocyte Proliferation: A Diagnosticand Therapeutic Challenge

Introduction: Drug induced leucopenia complicates any clinicalsituation especially when it's associated with COVID-19 infection.Here we report a case of vancomycin induced myeloid maturationarrest in a patient with COVID-19 infection where his conditionreverted to normal after stopping the drug.Aims &Objectives: It highlights the adverse effects of Vancomycinleading to promyelocyte proliferation posing a diagnostic challenge todifferentiate it from neoplastic promyelocyte proliferation.Materials &Methods: Case report: A 47 year old male presentedwith fever, dry cough and difficulty in breathing for 12 days. He wasCOVID-19 positive with CT lung showing bilateral pneumonic consolidations for which Vancomycin was started. Hemogram showedhemoglobin-6.8 gm/dl, total leucocyte count-3200/cumm with a differential count revealing: Neutrophil-28% (with left shift and featuresof dyspoiesis), Lymphocyte-66%, Monocyte-4%, Eosinophil-2%(Fig. 1a), and platelets-90,000/cumm. Bone marrow aspiration(BMA) and biopsy was advised. BMA was hypercellular for age withmarked promyelocyte proliferation &maturation arrest with strongMPO positivity (1b, c d). Bone marrow biopsy also reflected similarfindings (Fig-1e). FISH for PML-RARA translocation turned out to benegative, differentiating it from Acute promyeloytic Leukemia(Fig. 1f). A diagnosis of drug induced leucopenia with reactivepromyelocyte proliferation was made. Considering worsening of thesehematological findings, Vancomycin was stopped and patient'shematological findings improved drastically with stabilization ofhematological parameters.Result: Discussion: Drug induced leukopenia occurs in a dosedependent or dose-independent (idiosyncratic) reaction. Vancomycindependent antibodies against neutrophils lead to an autoimmunereaction directly affecting progenitor cell growth especially of myeloid cell lineage leading to maturation arrest. Secondly cytotoxicT-cell mediated response also has damaging effects on hematopoieticcells. Infections like COVID-19 can also lead to suppression ofnormal myeloid maturation due to release of interleukins.Conclusions: Myeloid maturation arrest with marked promyelocyteproliferation poses a diagnostic dilemma especially in patients presenting with cytopenia as they are confused with Acute promyelocytic Leukemia. This case highlights the importance of detailed knowledgerelated to drug induced myeloid maturation arrest which is reversibleafter stoppage of the offending drug.

Treatment of acute promyelocytic leukemia (APL) in a symptomatic patient with Coronavirus disease 19 (COVID-19) pneumonia

Introduction: In December 2019, a new variant of a coronavirus led to a pandemic outbreak. Patients with haematological malignancies are at high risk for a severe progression of COVID-19 with high mortality rates. Case report: 54-year-old patient was tested positive for COVID-19 upon admission. The CT scan showed bilateral ground-glass pulmonary opacities. He received dexamethasone and remdesivir. Due to severe thrombocytopenia and detection of blasts in peripheral blood a bone marrow biopsy was done. Cytological and molecular results confirmed the diagnosis intermediate risk APL. We started a therapy with arsenic trioxide and all-trans retinoic acid (ATO/ATRA). The white blood cells (WBC) increased and the respiratory situation worsened. The patient developed a thrombophlebitis. Bleeding complications appeared as an epistaxis, which required an intervention. 28 days after starting the induction, the bone marrow biopsy showed < 5% blasts. A complete peripheral remission was documented on day 50. Discussion: A major concern in treating APL is the differentiation syndrome, which can ultimately result in pulmonary failure. This patient presented with severely impaired lung function due to simultaneous COVID-19 pneumonitis. Therapy of APL had to consider both clinical conditions. Key decisions were (beyond antiviral therapy and supportive measures) a consequent dosing of glucocorticoids and early cytoreductive therapy using hydroxyurea (HU). The pulmonary function was critical during days 7-15 after start of APL therapy, consistent with differentiation syndrome being the main cause of worsening, and clinically met by stop of ATO/ATRA. Another concern was coagulation dysfunction, given the high risk of thromboembolic complications associated with COVID-19, the severe thrombocytopenia and plasmatic coagulation disorder caused by APL. In this case - besides supportive platelet transfusions - we treated by low dose heparin only when a thrombophlebitis occurred. Overall in this patient presenting with COVID-19 and simultaneously APL, the most challenging problem was overcoming pulmonary worsening in the initial phase of APL therapy.

Clinical Characteristics and Outcomes of Patients with Newly Diagnosed De Novo Acute Myeloid Leukemia (AML) during the COVID-19 Pandemic

Introduction The COVID-19 pandemic disrupted non-urgent and preventive medical care. During the early peak of the pandemic, an estimated 41% of US adults delayed or avoided medical care (Czeisler et al, CDC, 2020). While there were documented declines in the number of emergency department visits for myocardial infarction, stroke and hyperglycemia, similar data is not available related to acute myeloid leukemia (AML) (Lange et al, CDC, 2020). A delay in the diagnosis of AML could lead to presentation when patients are less able to withstand chemotherapy or have a higher disease burden which could compromise overall survival (OS). In this retrospective analysis, we aim to elucidate if there was a difference in clinical, cytogenetic, or molecular presentations and if there was an effect on early mortality as determined by overall survival at 1 and 6 months. Methods We compared the clinical, cytogenetic, and baseline molecular genetics of consecutive adult patients diagnosed with de novo AML at Dana-Farber Cancer Institute/Brigham and Women's (DFCI/BWH) Hospital from March 23, 2020, the date of the Massachusetts COVID State of Emergency, to August 23, 2020 to a historical cohort of similar patients between presenting between March 23, 2017 and August 23, 2020. Data was obtained from the Hematological Malignancy Data Repository and via review of the medical record. Patients were excluded from this cohort if they were diagnosed with acute promyelocytic leukemia, had known antecedent myeloid malignancy, or if they did not have DFCI/BWH 96-gene next-generation sequencing panel (RHP) performed at the time of diagnosis. Baseline clinical, laboratory, cytogenetic, and molecular characteristics and outcomes were compared between the pre-pandemic and pandemic cohorts using chi-squared, Fisher's exact, and Wilcoxon rank sum analyses (where appropriate) at a significance of p<0.05. Results Thirty-eight AML patients presented during the COVID-19 pandemic (PAN) and 308 in the pre-pandemic (PREPAN) period. There was no statistically significant difference in the monthly rate of new patients presenting in PREPAN and PAN cohorts (8 vs. 6 new patients/month, p=0.73). The median age at presentation (64 PREPAN vs. 65 PAN, p=0.77), sex, and therapeutic approach (intensive, non-intensive, supportive care, other) were not statistically different between cohorts. Presenting white blood cell count, platelet count, and fibrinogen were not different between cohorts, while hematocrit was significantly lower in the PAN cohort (23.8% vs. 26.0%, p=0.001). There was a trend for a higher median blast percentage (28.5% vs. 13%, p=0.09) in the PAN cohort. There were no differences between the cohorts in the median number of cytogenetic abnormalities, nor in the incidence of complex karyotype, (25.3% vs. 23.7%) across PREPAN and PAN respectively. There were also no significant differences in the European LeukemiaNet (ELN) risk classification scores across the PREPAN and PAN time periods, with 57.8% vs. 52.6% of total patients presenting with adverse risk disease respectively. When specific mutations of TP53, NPM1, and FLT3 were evaluated, only FLT3 demonstrated a statistical difference with a higher proportion in the pandemic group (p=0.04). OS at 1-month (97.4% and 93.2%, p=0.15) and 6-months (71.1% and 75.0%, p-0.87) were not statistically different in the PREPAN and PAN cohorts, respectively. Conclusion These data represent a novel analysis of the presenting clinical, cytogenetic and molecular characteristics of de novo AML during the COVID-19 pandemic. In contrast to other diseases, we did not see fewer de novo AML presentations during the peak of the COVID pandemic. While the reasons are unknown and require validation in large cohorts, the symptoms of leukemia including symptomatic anemia (low hematocrit) and higher WBC and blast count possibly driven by FLT3 mutations may drive patients to seek emergent clinical evaluation despite COVID pandemic barriers. The lack of difference in cytogenetic or other prognostic entities may demonstrate a lack of ymptom correlation causing patients to present for care. The higher incidence of FLT3 mutations and lower hematocrit could reflect more symptomatic presentation of AML during the COVID pandemic. Since these differences may be a surrogate for a higher disease burden, it will be important to compare outcomes at longer time points. [Formula presented] Disclosures: DeAngelo: Pfizer: Consultancy;Novartis: Consultancy, Research Funding;Jazz: Consultancy;Incyte: Consultancy;Forty-Seven: Consultancy;Autolus: Consultancy;Amgen: Consultancy;Agios: Consultancy;Takeda: Consultancy;Glycomimetrics: Research Funding;Blueprint: Research Funding;Abbvie: Research Funding;Servier: Consultancy. Stone: Bristol Meyers Squibb: Consultancy;Astellas: Membership on an entity's Board of Directors or advisory committees;BerGen Bio: Membership on an entity's Board of Directors or advisory committees;Boston Pharmaceuticals: Consultancy;Innate: Consultancy;Foghorn Therapeutics: Consultancy;Gemoab: Membership on an entity's Board of Directors or advisory committees;Glaxo Smith Kline: Consultancy;Celgene: Consultancy;Elevate Bio: Membership on an entity's Board of Directors or advisory committees;OncoNova: Consultancy;Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees;Syndax: Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy;Agios: Consultancy, Research Funding;Amgen: Membership on an entity's Board of Directors or advisory committees;Aprea: Consultancy;Arog: Consultancy, Research Funding;Jazz: Consultancy;Macrogenics: Consultancy;Novartis: Consultancy, Research Funding;Actinium: Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy;Syros: Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy. Garcia: AstraZeneca: Research Funding;Prelude: Research Funding;Pfizer: Research Funding;Genentech: Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees;Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Winer: Abbvie: Consultancy;Takeda: Consultancy;Novartis: Consultancy.

Acute Respiratory Distress Syndrome in a Patient With Acute Promyelocytic Leukemia: Overlapping Between Differentiation Syndrome and COVID-19.

Differentiation syndrome (DS) is a relatively common and severe complication in acute promyelocytic leukemia (APL) patients undergoing induction therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). DS is a multisystem disorder with pulmonary involvement. The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is also a systemic disorder with similar pulmonary and other clinical manifestations as DS. Here, we report an APL case with overlapping between DS and COVID-19. After admission to the hospital, the patient was diagnosed with APL and underwent differentiation therapy with ATRA/ATO. In the meantime, COVID-19 was diagnosed with a positive polymerase chain reaction test of SARS-CoV-2 from an oropharyngeal swab. The patient developed acute respiratory distress syndrome, coagulopathy, and acute kidney injury, which fit the clinical pictures of both DS and COVID-19. The patient died at last and this complicate case imposed big challenges for clinicians due to the laboratory and imaging findings of DS disguised in the context of COVID-19. Therefore, comprehensive treatment strategy should be considered to balance the risk and benefit of differentiation therapy in the context of COVID-19.

Oral etoposide combined with oral arsenic plus retinoic acid for two cases with newly diagnosed high-risk acute promyelocytic leukemia during COVID19 pandemic.

Acute promyelocytic leukemia (APL) is a highly curable hematology malignancy. The major factor influence prognosis of APL is early deaths (ED) during the course of induction therapy, especially in high-risk APL. Therefore, effective reduction of white blood cells and correction of coagulation abnormalities are the key points of treatment for high-risk APL. Due to COVID19 pandemic in China since Jan 2020, some patients with hematologic malignancies suspected of COVID-19 infection had been isolated and traditional intravenous chemotherapy drugs is not available in isolated wards. We had explored a regimen of an oral etoposide to reduce the tumor burden for high-risk APL and dual induction with retinoic acid (ATRA) and oral arsenic realgar-Indigo nautralis formula (RIF), and finally two cases of high-risk APL patients received complete remission in one month. It is indicated that pure oral induction regimen: oral etoposide, ATRA and RIF provides a novel therapy in outpatient clinics.

A Case of Subacute Brain Hemorrhage and Disseminated Intravascular Coagulation Secondary to Acute Promyelocytic Leukemia in a Pediatric Patient.

Acute promyelocytic leukemia (APML), characterized by the reciprocal translocation between chromosomes 15 and 17 [t(15;17)], is a result of proliferation of myeloid cells maturation which is interrupted at the promyelocytic stage. The central, and the most important, distinguishing feature of APML is a predisposition to disseminated intravascular coagulation (DIC). The overall prognosis of APML is very good, with 90% of patients achieving complete remission. We find it important to remind pediatric practitioners, both in the ambulatory and urgent care room settings, of presenting signs and symptoms of leukemia, as well as, up-to-date on management of such fulminant scenarios as DIC. Intracranial hemorrhage (ICH) is one of the commonest, and frequently fulminant complication of APML seen after initiation of induction chemotherapy. We report on a young female presenting with non-specific upper respiratory illness symptoms and recurrent headache, who was found to already have ICH and to be in DIC in the setting of APML at the time of initial evaluation. This case illustrates importance of thorough assessment and prompt consideration of wide differential diagnosis, which became somewhat limited and biased towards web-based telemedicine in the COVID-19 pandemics era.