Co-occurrence of CML Blast Crisis and Severe COVID 19 Infection: A Case Report.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affecting multiple organ systems. It can cause severe cytokine storms leading to intensive care unit admission requiring mechanical ventilation. However, there have been few studies establishing the outcomes of chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitors who are infected with COVID-19. We present a 69-year-old male with a history of CML on imatinib therapy with COVID-19 who developed acute respiratory distress syndrome needing mechanical ventilatory support, shock requiring vasopressors, and worse outcome secondary to blast crisis.

Effectiveness of digital care platform CMyLife for patients with chronic myeloid leukemia: results of a patient-preference trial.

BACKGROUND: Two most important factors determining treatment success in chronic myeloid leukemia (CML) are adequate medication compliance and molecular monitoring albeit still being suboptimal. The CMyLife platform is an eHealth innovation, co-created with and for CML patients, aiming to improve their care, leading to an increased quality of life and the opportunity of hospital-free care. OBJECTIVE: To explore the effectiveness of CMyLife in terms of information provision, patient empowerment, medication compliance, molecular monitoring, and quality of life. METHODS: Effectiveness of CMyLife was explored using a patient-preference trial. Upon completion of the baseline questionnaire, participants actively used (intervention group) or did not actively use (questionnaire group) the CMyLife platform for at least 6 months, after which they completed the post-intervention questionnaire. Scores between the intervention group and the questionnaire group were compared with regard to the within-subject change between baseline and post-measurement using Generalized Estimating Equation models. RESULTS: At baseline, 33 patients were enrolled in the questionnaire group and 75 in the intervention group. Online health information knowledge improved significantly when actively using CMyLife and patients felt more empowered. No significant improvements were found regarding medication compliance and molecular monitoring, which were already outstanding. Self-reported effectiveness showed that patients experienced that using CMyLife improved their medication compliance and helped them to oversee their molecular monitoring. Patients using CMyLife reported more symptoms but were better able to manage these. CONCLUSIONS: Since hospital-free care has shown to be feasible in time of the COVID-19 pandemic, eHealth-based innovations such as CMyLife could be a solution to maintain the quality of care and make current oncological health care services more sustainable. TRIAL REGISTRATION: ClinicalTrials.gov NCT04595955 , 22/10/2020.

Impact of the COVID-19 pandemic on the regular follow-up and outcomes of patients with chronic myeloid leukemia in chronic-phase.

Introduction: COVID-19 immediately became a major consideration in the management of chronic myeloid leukemia (CML). The influence of such considerations on viral transmission rates and leukemic control remain to be explored. We conducted this study to identify these alterations and to investigate their clinical consequences. Methods: This was a cross-sectional study, performed at a single institution on CML patients who were interviewed with a survey. We compared variables concerning new attitudes in the pandemic era between the 12-month periods before and after the pandemic onset. Outcome data were attained from the hospital archives. Findings: The number of patients receiving regular outpatient care for CML in chronic phase was 210, 91% had achieved at least major molecular responses. We assessed survival, progression, number of clinical visits of all, performed the survey on 89% and evaluated molecular responses on 86.6% of these patients. The frequency of clinical and molecular monitoring was significantly reduced during the pandemic deviating significantly from the guidelines. Frequency of death, progression, loss of molecular response was not significantly increased during the pandemic era despite a few cases where the delay in assessment possibly played a role in the unfavorable outcomes. There were no COVID related deaths or disabilities. Conclusion: The case-based untoward events would have probably been better managed with a more efficient communication web between patients, hematologists, and the laboratory. Therefore, it seems reasonable to consider whether such communicative paths are functional before giving up on the set schedule of CML management at times of uncertainty.

Immunological Response to SARS-CoV-2 After Infection and/or Vaccination Among Chronic Myeloid Leukemia Patients - A Prospective Study

Context: Patients with hematologic malignancies have an increased risk of SARS-CoV-2 infection, severe COVID-19, and higher mortality rates. Objective(s): We investigated the immunological response to SARS-CoV-2 after infection and/or vaccination and explored the impact of treatment response on antibody levels. Design(s): We added a cohort of CML patients to the ongoing study SPARTA. We collected saliva and peripheral blood to measure levels of SARS-CoV-2 antigen and antibodies. Result(s): From 10-1-2021 to 3-31-2022, we prospectively enrolled 69 participants (32 with CML, 37 non-cancer) with similar sociodemographic characteristics. There was a significant difference in the frequency of previous SARS-CoV-2 infections, where the control group had a higher percentage of patients previously diagnosed with COVID-19 (18.8% vs. 84%). Nevertheless, there was no difference in the detection of SARS-CoV-2 at the time of enrollment (0% vs. 5.6%). SARS-CoV-2 antibodies, either IgG or neutralizing (nAB), were detected in most of the participants regardless of cancer status (IgG, 84.4% in the CML cohort and 91.7% in the non-cancer cohort;nAB, 84.4% vs. 88.9%). The two groups had comparable IgG (mean 160.8 vs. 157.5 Ru/mL) and nAB (mean 1,473 vs. 1,509 ng/ml) levels. Overall, IgG and nAB levels were significantly higher in subjects who received the last vaccine dose within 6 months compared to those who received it >=6 months previously (IgG, CML, mean 177.7 vs. 113.2, control 190.5 vs. 134.4;nAB, CML 1,784 vs. 951.9, control 2,066 vs. 1,335). Both groups had comparable mean antibody levels according to the time since the last dose (IgG, <=6 months, 177.7 vs. 190.5, >=6 months, 113.2 vs. 134.4;nAB, <=6 months, 1,784 vs. 2,066, >=6 months 951.9 vs. 1,335). There was no difference in the detection and levels of antibodies according to therapy with TKIs (IgG, mean 158.8 vs. 185.2;nAB, 1,515 vs. 1,883) or achieving MMR (IgG, mean 152.4 vs. 177.5;nAB, 1,447 vs. 1,686). Conclusion(s): The immunological response to SARS-CoV-2 among CML patients is comparable to that in non-CML subjects. TKI therapy and the response to treatment did not impact the development of antibodies. Moreover, antibody levels decreased over time, with the most significant drop after 6 months since the last immunization dose. Copyright © 2022 Elsevier Inc.

Results of a Vaccination Against COVID-19 by a Vector Based Vaccine Sputnik V in Patients With Chronic Myeloid Leukemia

Introduction: Effectiveness and safety of new vaccines against new COVID-19 infection in patients with chronic myeloid leukemia (CML) need evaluation. Aim: To evaluate prospectively adverse events (AEs) and antibody formation after vaccination against SARS-CoV-2 in CML patients in a single center. CML patients applied for outpatient/remote consultations were suggested to report the post-vaccination AEs after the vector-based vaccine GamCovidVac (Sputnik V). At least 3 weeks after the 2nd injection patients were administered a blood test for SARS-CoV-2 spike(S) protein-specific antibodies by a semi-quantitative immunoassay (ELISA) which was considered positive at cut-off index (CI)>1. Other available tests for antibody detection were allowed as well. Results: Nighty-five chronic phase CML patients with a median (Me) age 54 years (range 29-89), received Sputnik V (DEC.2020–JUL.2021), 40(42%) were males. Me CML duration was 8 years (range 0-20), 75(79%) patients received TKIs at vaccination, 20(21%) were off-therapy: 17(18%) in treatment-free remission, 3(3%) with CML onset. Seventeen (18%) patients had a prior history of COVID-19. AEs were reported in 53(56%) patients: local pain/discomfort -30(31.5%), weakness/drowsiness -29 (30.5%), fever and/or chills -28(29%), other AEs -10(12%): headache, heartbeat, limbs/back pain, herpes reactivation. General reactions stopped in 1-2 days. No severe or life-threatening AEs were observed. Antibodies were detected in 66(93%) of 71 patients by any method, Me time after 2nd injection was 31 days (range 5-179). ELISA test was positive in 48(94%) of 55 tested patients with Me CI 7.7 (range 1.1-12), consistent with values of healthy people. Three of 7 negative by ELISA patients (Me age 58 years (range 40-70)) revealed antibodies by other tests with levels slightly above threshold. A very weak reverse correlation of the antibody levels with post-vaccination time (r =- 0.32) and with age (r =- 0.28) was observed. Conclusions: Sputnik V vaccine showed no unexpected or severe AEs in CML patients. Seroconversion rate of about 93-94% was close to the 3-phase trial data (94-97%). No strong age-dependent/time-dependent correlation of antibody levels was found in the tested time period. Sputnik V vaccination is safe and acceptable in CML patients.

Anti-Inflammatory Activity of CIGB-258 against Acute Toxicity of Carboxymethyllysine in Paralyzed Zebrafish via Enhancement of High-Density Lipoproteins Stability and Functionality.

Background: Hyperinflammation is frequently associated with the chronic pain of autoimmune disease and the acute death of coronavirus disease (COVID-19) via a severe cytokine cascade. CIGB-258 (Jusvinza®), an altered peptide ligand with 3 kDa from heat shock protein 60 (HSP60), inhibits the systemic inflammation and cytokine storm, but the precise mechanism is still unknown. Objective: The protective effect of CIGB-258 against inflammatory stress of N-ε-carboxymethyllysine (CML) was tested to provide mechanistic insight. Methods: CIGB-258 was treated to high-density lipoproteins (HDL) and injected into zebrafish and its embryo to test a putative anti-inflammatory activity under presence of CML. Results: Treatment of CML (final 200 µM) caused remarkable glycation of HDL with severe aggregation of HDL particles to produce dysfunctional HDL, which is associated with a decrease in apolipoprotein A-I stability and lowered paraoxonase activity. Degradation of HDL3 by ferrous ions was attenuated by a co-treatment with CIGB-258 with a red-shift of the Trp fluorescence in HDL. A microinjection of CML (500 ng) into zebrafish embryos resulted in the highest embryo death rate, only 18% of survivability with developmental defects. However, co-injection of CIGB-258 (final 1 ng) caused the remarkable elevation of survivability around 58%, as well as normal developmental speed. An intraperitoneal injection of CML (final 250 µg) into adult zebrafish resulted acute paralysis, sudden death, and laying down on the bottom of the cage with no swimming ability via neurotoxicity and inflammation. However, a co-injection of CIGB-258 (1 µg) resulted in faster recovery of the swimming ability and higher survivability than CML alone injection. The CML alone group showed 49% survivability, while the CIGB-258 group showed 97% survivability (p < 0.001) with a remarkable decrease in hepatic inflammation up to 50%. A comparison of efficacy with CIGB-258, Infliximab (Remsima®), and Tocilizumab (Actemra®) showed that the CIGB-258 group exhibited faster recovery and swimming ability with higher survivability than those of the Infliximab group. The CIGB-258 group and Tocilizumab group showed the highest survivability, the lowest plasma total cholesterol and triglyceride level, and the infiltration of inflammatory cells, such as neutrophils in hepatic tissue. Conclusion: CIGB-258 ameliorated the acute neurotoxicity, paralysis, hyperinflammation, and death induced by CML, resulting in higher survivability in zebrafish and its embryos by enhancing the HDL structure and functionality.

Management of Newly Diagnosed Chronic Myeloid Leukemia During COVID-19 Hospitalization: A Teaching Case.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation of mature and maturing granulocytes. CML has the potential to cause secondary immunodeficiency in affected patients. COVID-19 infection has been associated with worse outcomes in immunocompromised patients, including patients with hematologic cancers, requiring hospitalization. Herein we present a 61-year-old male with known COVID-19 infection who presented for the evaluation of acute hypoxic respiratory failure and was found to have marked leukocytosis of 125,000. The patient was eventually diagnosed with CML, and his respiratory failure resolved with conventional COVID-19 pneumonia treatment. With this case report, we hope to assist clinicians in the workup of marked leukocytosis in the setting of COVID-19 pneumonia and aim to help clinicians in the management of patients admitted with COVID-19 pneumonia and concomitant CML.

SARS-CoV-2 Omicron Variant in Patients With Chronic Myeloid Leukemia: A Retrospective Study.

Background and aims Coronavirus disease 2019 (COVID-19) is caused by a virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first pandemic wave, SARS-CoV-2 had developed significant changes and mutations that resulted in the emergence of different strains. Each strain varies in its virulence and disease severity. Most reports have shown that the Omicron variant causes mild illness. Little is known about the impact of Omicron in patients with chronic myeloid leukemia. We present patients with chronic myeloid leukemia who had infection with the Omicron variant of the SARS-CoV-2 and their outcomes. Materials and methods  Retrospective data from the records of the National Center for Cancer Care and Research from December 20, 2021, to January 30, 2022. Participants were adults over the age of 18 years with Omicron infection who had been diagnosed with chronic myeloid leukemia according to World Health Organization classifications from 2008 and 2016. Results Eleven patients with chronic myeloid leukemia had Omicron infection. All patients had a mild disease according to the World Health Organization classification of COVID-19 severity. The majority of patients were young males.  Conclusions In patients with chronic myeloid leukemia, infection with the Omicron variant of the SARS-CoV-2 usually results in mild disease not requiring hospitalization.

Lymphoid blast crisis after prolonged treatment-free remission in chronic myeloid leukaemia after tyrosine kinase inhibitor de-escalation during the COVID-19 pandemic.

During the COVID-19 pandemic, access to health services has been considerably restricted and furthermore, patients have been reluctant to attend for routine monitoring, and this may have had a negative impact in the management of patients affected with haematological disorders. Sudden blast crisis in chronic myeloid leukaemia is categorized as a rapid onset of blastic phase, after a documented 'optimal' response to tyrosine kinase inhibitor (TKI) therapy and within 3 months of a normal complete blood count. Herein, we describe a case of patient who developed sudden blast crisis after TKI while in treatment-free remission.

Chronic Myeloid Leukemia in Children: Immune Function and Vaccinations.

Children with CML need TKI treatment for many years, and the lack of knowledge about immune dysfunction with TKI has hindered routine immunizations. This review attempts to provide an overview of the effects of TKIs licensed for children (e.g., imatinib, dasatinib, and nilotinib) on immune function, as well as its implications on immunizations. We discuss surveillance strategies (e.g., immunoglobulin blood serum levels and hepatitis B reactivation) and immunizations. All inactivated vaccines (e.g., influenza, pneumococcal, and streptococcal) can be given during the treatment of CML in the chronic phase, although their efficacy may be lower. As shown in single cases of children and adults with CML, live vaccines (e.g., varicella, measles, mumps, rubella, and yellow fever) may be administered under defined circumstances with great precautions. We also highlight important aspects of COVID-19 in this patient population (e.g., the outcome of COVID-19 infection in adults with CML and in children with varying hemato-oncological diseases) and discuss the highly dynamic field of presently available different vaccination options. In conclusion, TKI treatment for CML causes humoral and cellular immune dysfunction, which is mild in most patients, and thus infectious complications are rare. Routine immunizations are important for health maintenance of children, but vaccinations for children with CML on TKI therapy should be carefully considered.

HHV8-Negative Effusion-Based Large B Cell Lymphoma Arising in Chronic Myeloid Leukemia Patients under Dasatinib Treatment: A Report of Two Cases.

Tyrosine kinase inhibitors (TKIs) are the treatment of choice for BCR-ABL1-positive chronic myeloid leukemia (CML). Although TKIs have substantially improved prognosis of CML patients, their use is not free of adverse effects. Dasatinib is a second generation TKI frequently associated with pleural effusion in up to 33% of patients. This results in symptoms as dyspnea, cough and chest pain that may require therapy discontinuation. In the present report, we describe two exceptional cases of HHV8-negative large B-cell effusion-based lymphoma (EBL) confined to the pleura, incidentally, diagnosed in patients presenting with dasatinib-related pleural effusion. One patient (case 1) is alive and is in remission at 17 months from large B-cell EBL diagnosis while unfortunately the other patient (case 2) died of progressive disease and COVID-19 pneumonia 16 months from large B-cell EBL diagnosis. These cases raise concern about a possible association between large B-cell EBL and dasatinib, and the different clinical outcome of the two cases poses a challenge in treatment decision. For this reason, we strongly recommend cytological investigation in patients with persistent/relapsing pleural effusion under dasatinib, primarily to validate its possible association with lymphoma development and to improve the knowledge about this entity.

Tyrosine Kinase Inhibitors Play an Antiviral Action in Patients Affected by Chronic Myeloid Leukemia: A Possible Model Supporting Their Use in the Fight Against SARS-CoV-2.

SARS-CoV-2 is the viral agent responsible for the pandemic that in the first months of 2020 caused about 400,000 deaths. Among compounds proposed to fight the SARS-CoV-2-related disease (COVID-19), tyrosine kinase inhibitors (TKIs), already effective in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML), have been proposed on the basis of their antiviral action already demonstrated against SARS-CoV-1. Very few cases of COVID-19 have been reported in Ph+ ALL and in CML Italian cohorts; authors suggested that this low rate of infections might depend on the use of TKIs, but the biological causes of this phenomenon remain unknown. In this study, the CML model was used to test if TKIs would sustain or not the viral replication and if they could damage patient immunity. Firstly, the infection and replication rate of torquetenovirus (TTV), whose load is inversely proportional to the host immunological control, have been measured in CML patients receiving nilotinib. A very low percentage of subjects were infected at baseline, and TTV did not replicate or at least showed a low replication rate during the follow-up, with a mean load comparable to the measured one in healthy subjects. Then, after gene expression profiling experiments, we found that several "antiviral" genes, such as CD28 and IFN gamma, were upregulated, while genes with "proviral" action, such as ARG-1, CEACAM1, and FUT4, were less expressed during treatment with imatinib, thus demonstrating that TKIs are not detrimental from the immunological point of view. To sum up, our data could offer some biological explanations to the low COVID-19 occurrence in Ph+ ALL and CML patients and sustain the use of TKIs in COVID-19, as already proposed by several international ongoing studies.

SARS CoV 2 infection in chronic myelogenous leukemia: Severe hematological presentation.

Infection with SARS-CoV-2, the cause of coronavirus infectious disease-19 (COVID-19), has caused a pandemic. Few data are available about the risk of COVID-19 infection in persons with hematological cancer, but controversy whether these persons have the same clinical signs and outcomes. We describe a case of life-threatening COVID-19 infection complicated by severe anemia in patients affected also by chronic myelogenous leukemia. The screening for RBC antibodies and the direct antiglobulin test (DAT) turned positive. The identification of the antibodies, showed the presence of an alloantibody with anti-Lewis b specificity, which was reactive at room temperature, in the anti-human globulin phase (AGH) and with papain-treated red blood cells. At the same time hemophagocytic lymphohistiocytosis (HLH), on the basis of major laboratory findings including hyperferritnemia, increase of triglicerides levels and according to the HLH score was suspected. Patients received antiviral therapy, steroids and intravenous immunoglobulins. Hemolysis resolved and ferritin dramatically decreased after administration of Ig and a Afull recovery was achieved after viral infection resolution.This case highlights the novel and multifaceted hematological findings during sever COVID 19 infection. COVID 19-related pneumonia is mediated by hyper activation of effector T cells and excessive production of inflammatory cytokines, such as IL-6, IL-1, interferon-gamma, and TNF. This inflammatory process called "cytokine storm" is a life-threatening complication of COVID 19 infection. In this case severe immunohematological consequences are reported for the first time and recognition of this complications are probably underestimated.