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1.
Scand J Immunol ; 95(4): e13153, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1784739

ABSTRACT

Infections with SARS-CoV-2 have been unduly severe in patients with haematological malignancies, in particular in those with chronic lymphocytic leukaemia (CLL). Based on a series of observations, we propose that an underlying mechanism for the aggressive clinical course of COVID-19 in CLL is a paucity of plasmacytoid dendritic cells (pDCs) in these patients. Indeed, pDCs express Toll-like receptor 7 (TLR7), which together with interferon-regulatory factor 7 (IRF7), enables pDCs to produce large amounts of type I interferons, essential for combating COVID-19. Treatment of CLL with Bruton's tyrosine kinase (BTK) inhibitors increased the number of pDCs, likely secondarily to the reduction in the tumour burden.


Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , COVID-19/complications , Dendritic Cells , Humans , Interferon Regulatory Factor-7 , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , SARS-CoV-2 , Toll-Like Receptor 7
2.
Haematologica ; 107(3): 625-634, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1714970

ABSTRACT

Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.


Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , RNA, Messenger/genetics , SARS-CoV-2
3.
Clin Immunol ; 236: 108936, 2022 03.
Article in English | MEDLINE | ID: covidwho-1650423

ABSTRACT

A 52-year-old male patient who was diagnosed with chronic lymphocytic leukemia two years ago; admitted to our hospital with complaints of fever (>38C), shortness of breath, and fatigue. He was receiving fludarabine, cyclophosphamide, and rituximab (FCR) regimen for one year after two courses of cyclophosphamide, vincristine, and prednisolone (CVP) regimen. The patient was diagnosed with COVID-19 associated cytokine storm and tocilizumab 800 mg was administered in addition to corticosteroids. Significant improvement was observed in both clinical and laboratory parameters and his hypoxemia resolved. The patient whose complaints recurred on the 13 th day of discharge was admitted to the hospital again with severe hypoxemia (oxygen saturation < 90) and fever (>38C). Pulse steroid (250 mg methylprednisolone for three days, followed by 40 mg/day) and anakinra 400 mg/day intravenously were started. Despite the treatment, the patient progressed to respiratory failure and died on the sixth day of second hospitalization.


Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Antineoplastic Combined Chemotherapy Protocols , COVID-19/complications , COVID-19/drug therapy , Cyclophosphamide/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Methylprednisolone/therapeutic use , Middle Aged , Rituximab/therapeutic use , Treatment Outcome
4.
Curr Oncol Rep ; 24(2): 209-213, 2022 02.
Article in English | MEDLINE | ID: covidwho-1641007

ABSTRACT

PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative disease in the elderly of the western world. Immune defective responses and treatment can worsen the immune system's competence of CLL patients. Consequently, they may present a higher incidence of recurrent severe infections, second malignancies, and reduced efficacy of vaccines. The outbreak of COVID-19 is an ongoing pandemic, and patients with comorbidities experience more severe forms of the disease. Hematological malignancies are associated with higher case fatality rates (CFRs) than other cancers. Knowledge about COVID-19 incidence, clinical course, and immune response to the infection and vaccination in CLL may contribute to design strategies that improve the outcomes of patients in the future. RECENT FINDINGS: The prevalence of SARS-CoV-2 positivity in CLL is not significantly higher than seen in the general population. CFRs for CLL patients are 16.5-fold more elevated than the median reported worldwide and even higher in older patients, those who require hospitalization have significant comorbidities or need oxygen therapy. CLL status decreases the anti-SARS-CoV-2 positivity after infection or vaccination by around 40%, and the spike-specific antibody titers are 74-fold lower than healthy age-matched controls. The response rate to COVID-19 vaccines is even worse in patients with active CLL-directed therapies like BTKi, BCL-2 antagonists, or anti-CD20 monoclonal antibodies. CLL patients are at a greater risk of death from COVID-19. Inherent immunosuppression of CLL and immune deficiencies caused by treatment significantly decrease the ability to produce natural or vaccine-induced anti-SARS-CoV-2 immune responses.


Subject(s)
COVID-19/epidemiology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Middle Aged , SARS-CoV-2/immunology , Vaccination
6.
Blood Adv ; 6(1): 207-211, 2022 01 11.
Article in English | MEDLINE | ID: covidwho-1542102

ABSTRACT

Immunocompromised individuals such as patients with chronic lymphocytic leukemia (CLL) are at risk of impaired immune responses to vaccination. The objective of our study was to evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses in patients with CLL after the first, second, and third doses of the BNT162b2 or mRNA-1273 vaccines and after a single dose for patients with confirmed previous COVID-19. In all, 530 patients were included in the study. Patients received 2 doses at a 4-week interval and a third dose if they were seronegative after the second dose. Response rate was 27% after dose 1 and 52% after dose 2. Post-dose 2 treatment-naïve patients had the highest response rate (72%) followed by patients previously treated by chemoimmunotherapy (60%). Among patients receiving therapy, those receiving Bruton tyrosine kinase inhibitor alone (22%) or in combination with anti-CD20 monoclonal antibodies or venetoclax (0%) had the poorer response rate whereas patients who received venetoclax monotherapy achieved a significantly higher response rate (52%). A multivariable analysis identified age older than 65 years, ongoing CLL treatment, and gamma globulin ≤6 g/L as independent predictors of the absence of seroconversion. Post-dose 2 seronegative patients had a global response rate of 35% after dose 3. This study provides an argument for the use of a third dose and for prophylactic SARS-CoV-2 neutralizing monoclonal antibodies.


Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Aged , Antibodies, Viral , COVID-19 Vaccines , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , RNA, Messenger/genetics , SARS-CoV-2
10.
Expert Rev Hematol ; 14(9): 819-830, 2021 09.
Article in English | MEDLINE | ID: covidwho-1349725

ABSTRACT

INTRODUCTION: Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy. AREAS COVERED: The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism. EXPERT OPINION: Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.


Subject(s)
Adenine/analogs & derivatives , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Adenine/adverse effects , Adenine/pharmacology , Adenine/therapeutic use , Aged , COVID-19/complications , Disease Management , Drug Interactions , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/therapy , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Piperidines/adverse effects , Piperidines/pharmacology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology
11.
Haematologica ; 107(3): 625-634, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1332108

ABSTRACT

Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.


Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , RNA, Messenger/genetics , SARS-CoV-2
15.
Blood ; 137(2): 185-189, 2021 01 14.
Article in English | MEDLINE | ID: covidwho-953565

ABSTRACT

Vaccinations are effective in preventing infections; however, it is unknown if patients with chronic lymphocytic leukemia (CLL) who are treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitors (BTKi's) respond to novel adjuvanted vaccines. Understanding the effect of BTKi's on humoral immunity is timely because BTKi's are widely used and vaccination against coronavirus disease 2019 is urgently needed. In 2 open-label, single-arm clinical trials, we measured the effect of BTKi's on de novo immune response against recombinant hepatitis B vaccine (HepB-CpG) and recall response against recombinant zoster vaccine (RZV) in CLL patients who were TN or on BTKi. The primary end point was serologic response to HepB-CpG (anti-hepatitis B surface antibodies ≥10 mIU/mL) and RZV (≥fourfold increase in anti-glycoprotein E). The response rate to HepB-CpG was lower in patients on BTKi (3.8%; 95% confidence interval [CI], 0.7-18.9) than patients who were TN (28.1%; 95% CI, 15.6-45.4; P = .017). In contrast, the response rate to RZV did not differ significantly between the BTKi (41.5%; 95% CI, 27.8-56.6) and TN cohorts (59.1%; 95% CI, 38.7-76.7; P = .2). BTKi's were associated with a decreased de novo immune response following HepB-CpG, whereas recall immune response following RZV was not significantly affected by BTKi therapy. These trials were registered at www.clinicaltrials.gov as #NCT03685708 (Hep-CpG) and #NCT03702231 (RZV).


Subject(s)
Hepatitis B Vaccines/immunology , Herpes Zoster Vaccine/immunology , Immunity , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Protein Kinase Inhibitors/adverse effects , Vaccines, Synthetic/immunology , Adjuvants, Immunologic , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Aged , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Patient Outcome Assessment , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Vaccination
17.
Clin Cancer Res ; 26(14): 3514-3516, 2020 07 15.
Article in English | MEDLINE | ID: covidwho-693869

ABSTRACT

As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Coronavirus Infections/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, B-Cell/drug therapy , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Anti-Inflammatory Agents/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/pathology , Humans , Inflammation/prevention & control , Macrophages/immunology , Pandemics , Piperidines/therapeutic use , Pneumonia, Viral/pathology , Protein Kinase Inhibitors/adverse effects , Pyrazines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2
19.
J Infect Dis ; 222(7): 1103-1107, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-663915

ABSTRACT

The antiviral drug remdesivir has been shown clinically effective for treatment of COVID-19. We here demonstrate suppressive but not curative effect of remdesivir in an immunocompromised patient. A man in his fifties treated with chemoimmunotherapy for chronic lymphocytic leukemia experienced a 9-week course of COVID-19 with high fever and severe viral pneumonia. During two 10-day courses of remdesivir starting 24 and 45 days after fever onset, pneumonia and spiking fevers remitted, but relapsed after discontinuation. Kinetics of temperature, C-reactive protein, and lymphocyte counts mirrored the remitting/relapsing SARS-CoV-2 infection. Combination therapy or longer treatment duration may be needed in immunocompromised patients.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Pneumonia, Viral/drug therapy , Severe Acute Respiratory Syndrome/drug therapy , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Fever/drug therapy , Fever/virology , Humans , Immunocompromised Host , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/virology , Time Factors , Treatment Outcome
20.
Leukemia ; 34(9): 2354-2363, 2020 09.
Article in English | MEDLINE | ID: covidwho-638239

ABSTRACT

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.


Subject(s)
Betacoronavirus , Coronavirus Infections/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Pneumonia, Viral/pathology , Adenine/analogs & derivatives , Age Factors , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , COVID-19 , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Pandemics , Piperidines , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Prognosis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Surveys and Questionnaires
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