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Clinical Infection & Immunity

Case Report

Volume 6, Number 1, March 2021, pages 18-23

Report on a COVID-19 Case and Concurrent Diagnosis of Chronic Myelogenous Leukemia

Chronic myeloid leukemia (CML) accounts for 15% of leukemias in adults. The median age at the time of diagnosis is 67 years old [1]. This disease is the result of a reciprocal translocation between chromosomes 9 and 22 (t(9;22)), called Philadelphia chromosome (Ph), which results in the fusion gene breakpoint cluster region- Abelson 1 (BCR-ABL1), which has tyrosine kinase activity responsible for the physiopathology of the disease (proliferation and decrease of apoptosis).

Advanced age and comorbidities such as diabetes, heart disease, lung disease and nephropathy are correlated with high mortality rates due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Immunocompromised patients are considered to be at risk for developing severe symptoms from this disease [2].

Chronic phase CML (CML-FC) or tyrosine kinase inhibitors (TKIs) do not induce a clinically relevant state of immune suppression, so it is assumed that patients with CML-FC treated with TKIs are not at a higher risk of developing severe SARS-CoV-2 infection.

It is even noted that imatinib may have anti-coronavirus activity at two points in the virus’ life cycle. In early stages of infection, it inhibits the fusion of the virus with the endosome and subsequent release into the cytoplasm, preventing viral entry and replication. In the late phase of the infection, the expression of the ABL2 protein allows the replication of SARS-CoV-2, and this protein is inhibited by the TKI [3].

A 43-year-old man, obesity grade II (body mass index (BMI) 36), diabetic, with a 10-day evolution chart, is characterized by pharyngodynia, general malaise, asthenia, adinamia and fever up to 39 °C, so the patient decided to consult a physician, who prescribed erythromycin and ciprofloxacin for 7 days. He did not improve and started suffering from dyspnea at rest, so he went to the emergency department of the Hospital General Regional No. 72 of the Instituto Mexicano del Seguro Social on August 23, 2020. After admission, he had O₂ saturation 80%, blood pressure 109/78 mm Hg, heart rate 69/min, respiratory rate 25/min and a temperature of 37 °C. Clinical determination showed altered short-term memory, symmetrical chest with decreased breath sounds and bilateral basal rales. Abdominal palpation revealed liver 3 cm below costal ridge and spleen 2 cm below costal ridge. Laboratory results showed leukocytes 122 × 10⁹/L, erythrocytes 5.2 M/µL, hemoglobin 14.7 g/dL, hematocrit 49.59%, mean corpuscular hemoglobin 28.17 pg, mean corpuscular volume (MCV) 95.03 fL, neutrophils 61 × 10⁹/L, lymphocytes 3.3 × 10⁹/L, immature cells 40% (promonocytes, promyelocytes, myelocytes), basophils 1%, eosinophils 1%, monocytes 5%, platelets 390 × 10⁹/L, TP 14.10/s, thrombotic thrombocytopenic purpura (TTP) 24.20/s, D-dimer 380, fibrinogen 794 mg/dL, creatinine 2.1 mg/dL, urea 156 mg/dL, formic acid (FA) 62 U/L, globulins 3.1 g/dL, glucose 238 mg/dL, glycosylated hemoglobin A1c 6.6%, lactate dehydrogenase (LDH) 725 U/L (normal range: 230 - 460 U/L), total proteins 7.09 g/dL, chlorine 96 mmol/L, Na 132 mmol/L, K 4.3 mmol/L, blood urea nitrogen (BUN) 73.32 mg/dL, general urine test without alterations, hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) non reactive, and toxopasma, rubella, cytomegalo, herpessimplx (TORCH) profile with immunoglobulin (IgG) for cytomegalovirus and rubella. Cabinet showed posteroanterior (PA) chest radiography with alveolo-interstitial condition, bilateral, diffuse. SARS-CoV-2 infection was suspected and hospitalization was decided. Thorax tomography showed generalized bilateral alveolo-interstitial affectation with tarnished glass pattern and consolidations of subpleural predominance, with air bronchogram, compatible with COVID-19 viral pneumonia (COVID-19 reporting and data system (CORADS) 5). Semi-quantitative affectation score was as follows: upper lobe 4 points, middle 3 points, lower 4 points, left lobe 4 points and lower 4 points (Fig. 1).

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Figure 1. Tomography of the patient’s chest in sagittal, coronal and axial sections with the presence of a bilateral ground glass pattern of peripheral disposition and multifocal consolidations compatible with viral pneumonia due to coronavirus disease 2019 (COVID-19), COVID-19 reporting and data system (CORADS) 5.

Abdominal ultrasound showed grade 2 hepatic steatosis and splenomegaly (13.7 cm).

The diagnosis of SARS-CoV-2 infection was corroborated with reverse transcription-quantitative polymerase chain reaction (RT-QPCR). Due to the findings in the hematic biometry, a directed interrogation was carried out which revealed diaphoresis predominantly nocturnal of 4 months of evolution and loss of weigth of 10 kg in 1 month, without any other symptomatology. He was evaluated on August 24, 2020 by the hematology service, which performed peripheral blood smears and found a leukoerythroblastic pattern with eosinophils 2%, basophils 1% and blasts 1%. Likewise, bone marrow aspiration was performed with 100% cellularity, granulocytic hyperplasia, myeloid/erythroid ratio 10:1, eosinophils 3%, basophils 1% and blasts 2.5%, which concluded chronic myeloproliferative neoplasia, probably CML (Fig. 2).

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Figure 2. Marrow smear. In this illustration, there is a pronounced increase in the total white blood cell count. There is a predominance of myelocytes and immature myeloid cells. Wright × 100 stain.

On August 26, 2020, the diagnosis of CML was confirmed with reverse transcription-polymerase chain reaction (RT-PCR) BCR-ABL1 of 69.5% ischemic stroke (IS) and karyotype with 46,XY, t(9;22)(q34;q11.2) in all the metaphases (n = 20). Therefore, we determined CML in chronic phase, with low risk for Sokal, Hasford (Euro) and European Treatment Outcome Study (EUTOS).

During his hospitalization, treatment for SARS-CoV-2 consisted of an O₂ mask with reservoir at 10 L/min, thromboprophylaxis with low molecular weight heparin, dexamethasone 6 mg every 24 h for 10 days, imipenem 500 mg every 8 h for 7 days and strict management of liquids, electrolytes and leukemic control. On the 10th day of antibiotic therapy, diarrheal evacuation with mucus was present, so it was decided to administer metronidazole orally for suspicion of C. difficile infection, which received satisfactory response.

On the other hand, on August 24, 2020, concomitant cytoreductive hematological treatment was started with hydroxycarbamide at a dose of 500 mg every 8 h. Its evolution was satisfactory in terms of SARS-CoV-2 infection and its complications and CML, so it was decided to discharge him to home on September 9, 2020, with hydroxycarbamide 500 mg every 24 h for a reduction in the number of leukocytes of 18 × 10⁹/L, as well as supplementary oxygen and an appointment at the hematology outpatient service.

The patient is currently under outpatient surveillance. He was seen on September 23, 2020 with complete hematological response. Hydroxcarbamide was stopped and imatinib was started at a standard dose of 400 mg/day (the start date of the TKI was due to required administrative procedures). RT-PCR for BCR-ABL1 will be performed after 3 months with imatinib treatment to assess early molecular response.

CML has an incidence of one to two cases per 100,000 adults, represents 15% of the leukemias diagnosed in the United States [1] and has reached an incidence of 180,000 cases in 2020 (American Cancer Society), with a decreasing mortality of 10-20% to 1-2% [4]. The median age at the time of diagnosis is 67 years old, however, it has been reported in all age groups. In Mexico, it occurs in one out of every 100,000 adults and represents 4% of the incidence of all types of cancers. It affects adults between 55 and 60 years old; however, there are national reports showing the median age is 39 years old, with 2% annual prevalence and 5% mortality [5].

CML is defined by the presence of the Ph, resulting from the reciprocal translocation between chromosomes 9 and 22 (t(9;22)), which originates from the BCR-ABL1 fusion gene.

Up to 50% of patients are asymptomatic and are diagnosed incidentally after a routine laboratory study [6-8]. When clinical manifestations are present, they are usually nonspecific. The most frequent sign is splenomegaly present in 46-76% of patients, which can cause pain in the upper left quadrant or early satiety. Other clinical data are fatigue, nocturnal diaphoresis, anemia and hemorrhage due to platelet dysfunction (more common in patients with marked thrombocytosis), and less than 5% of patients present symptoms secondary to leukostasis, such as priapism, which is more frequent when the leukocyte count exceeds 250,000/µL [9].

The characteristics of the hematic biometry are the following: absolute leukocytosis (median 100,000/µL) with a left shift and predominance of myeloids (more myelocytes than mature metamyelocytes observed in the peripheral blood smear); the presence of blasts is usually < 2%; absolute basophilia is almost universal, with absolute eosinophilia in 90% of the cases [10]. The existence of monocytosis is more prominent in the unusual cases with a BCR-ABLp190. The platelet count is usually normal or elevated, and thrombocytopenia suggests another diagnosis or the presence of a disease in an advanced stage [11].

The initial evaluation involves the complete clinical history and a physical examination, as well as blood biometry with differential and chemical profile. It is necessary to perform a bone marrow aspiration and to take a bone biopsy for its morphological and cytogenetic evaluation. Likewise, the presence in peripheral blood of the BCR-ABL1 transcript should be established and quantified by a standardized RT-PCR test [12].

CML can present three clinical phases (chronic, accelerated and blastic). The most prevalent phase at diagnosis is the chronic phase. At the time of diagnosis, it is essential to classify patients according to their prognostic risk (low, intermediate or high) by means of the Sokal, Hasford (Euro) and EUTOS scores [13, 14].

TKIs have transformed CML outcomes and significantly improved overall survival, event free survival and progression free survival rates [15, 16]. It is frequent that, while the diagnosis is confirmed and if there is a high tumor load, cytoreduction with hydroxycarbamide is initiated, as in the case of our patient.

Currently the most important prognostic factor is the response to treatment, so monitoring is extremely important. At the beginning, cell counts are performed every 2 weeks until a complete hematological response is obtained, which also allows the timely detection of toxicity secondary to treatment. Later, based on the current guidelines of European Leukemia Net 2020, monitoring is done by standardized RT-PCR for quantification of BCR-ABL1 transcripts, initially after 3, 6 and 12 months in order to evaluate an optimal response. Cytogenetics is important at the diagnosis to search for additional chromosomal abnormalities.

CML has been linked to a variety of bacterial and viral infections. Viral infections include adenoviruses, viruses belonging to the herpesviridae family, and HIV, which appear in case reports. However, these infections have been associated with inducible tyrosine kinase (ITK) therapy, especially imatinib, more than with the disease [7, 17]. In the case of adenoviruses, they have been recognized as clonal activators of different types of leukemias. In a Venezuelan project, the molecular mimicry between this kind of virus and the structure of the human leukocyte antigen DRB1 (HLA-DRB1)*14 antigen, the most common one found in its population with a link to CML, was studied. This suggests that the interaction contributes to the increase of self-reactive memory TCD8⁺ cells and DRB1*14 lymphocytes involved in the abnormal clonality of these patients [18]. On the other hand, there is evidence of the association between CML and tuberculosis for the last 10 years, and it is well known that patients with CML have an increased risk of suffering intrapulmonary or extrapulmonary tuberculosis (hazard ratio(HR) of 3.76), with an incidence of 40.1/10,000 [19]. This is reported in individuals who have undergone transplantation of hematopoietic parents (risk up to nine times), so there is an increased mortality, a situation not related to treatment with KTIs [20].

In December 2019, several cases of a new respiratory disease were described, which led to the detection of a coronavirus outbreak in December 2019 originated in Wuhan, Hubei Province in the People’s Republic of China [21]. A new strain was confirmed in January 2020 and it was named SARS-CoV-2, which was related to the SARS-CoV of the 2002 - 2003 outbreak [22]. COVID-19 was rapidly transmitted from Wuhan to other parts of the world. The rapid increase in cases globally led the WHO to declare an emergency (pandemic) on January 30, 2020 [21-23].

To date (November 8, 2020), WHO reported the global number of COVID-19 cases has increased by 8%, with more than 3.6 million new cases, while new deaths have increased by 21% to more than 54,000. This brings the cumulative number to more than 49.7 million reported cases and more than 1.2 million deaths worldwide [24].

SARS-CoV-2 is known to belong to the order Nidovirales, family Coronaviridae, subfamily Coronavirinae. The latter consists of four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus [25].

They are enveloped viruses with an approximate diameter of 125 nm, single-stranded RNA genome and positive direction. It encodes four structural proteins including glycoprotein (S), envelope (E), membrane (M) and nucleocapsid (N), as well as 16 non-structural proteins involved in viral replication. The entry site of the virus is mainly the respiratory mucosa. It replicates through angiotensin converting enzyme receptors and mounts an innate, cellular and humoral immune response. It affects multiple organs, such as lungs, heart, central nervous system, kidney and endothelium. It has been associated with acute respiratory failure syndrome, cardiovascular risk, and high mortality [26].

Regarding the hematopoietic system, lymphopenia was initially recognized as the most common condition in critically ill patients in Wuhan, China, followed by clotting disorders such as arterial and venous thrombosis. Consequently, treatment was optimized to avoid these complications [27, 28].

In recent months it has been observed that patients with leukemia are at exceptionally high risk of developing COVID-19. Lethality rates of up to 37% have been reported in patients with hematological malignancies and COVID-19 [29]. Although the exact incidence of COVID-19 in cancer patients in general and in leukemia patients in particular is not clear, it is important to mention that each subtype of leukemia has risk factors for COVID-19 due to its biology or treatment, for example: hypogammaglobulinemia, functional deficiency of B cells due to the use of monoclonal anti-CD20 antibodies, prolonged exposure to steroids, pulmonary and renal failure, cardiac dysfunction due to exposure to anthracyclines, increased risk of asparaginase thrombosis and myelosuppression. This leads to an increase in mortality, a situation observed particularly in patients with acute leukemias [30].

In Hubei, China, a study was conducted to identify the association between CML and COVID-19. It found a prevalence of COVID-19 in people with CML of 0.9% (0.1-1.8%), a higher percentage compared to the population without CML but lower than those hospitalized with oncohematological diseases. This study reported increased susceptibility in patients who were in an advanced stage of the disease, but not in patients who were immunosuppressed with TKIs [2]. In Italy, these reports were followed up and the possible protective effect of imatinib was evaluated in patients who had COVID-19. It is believed that the anticoronavirus activity can be present in two points of the virus life cycle. In early stages of the infection, it inhibits the fusion of the virus with the endosome and the subsequent release in the cytoplasm, which prevents viral entry and replication. In the late phase of the infection, the expression of the ABL2 protein allows the replication of SARS-CoV, and this protein is inhibited by the TKI [3].

A randomized study is currently under development to try to solve this hypothesis (European Union Drug Regulating Authorities Clinical Trials (EudraCT) 2020-001236-10). The adverse factors associated with an increased risk of developing COVID-19 among people with CML in the above-mentioned study from Hubei, China, were exposure to a SARS-CoV-2 infected person (P = 0.037), no complete hematologic response (P = 0.003), and the presence of comorbidities (P = 0.024). Likewise, there was a greater risk of developing COVID-19 in subjects in an advanced phase of CML [3-31].

We present the case of a patient who developed a COVID-19 infection. During his hospitalization, he was diagnosed with CML. There is limited information on the frequency of SARS-CoV-2 infection in patients with CML and even more so in de novo disease. Likewise, it is necessary to know the determining factors in the evolution, the daily management of the patient, follow-up, the possible long-term complications, and the treatment decisions of patients with CML and COVID-19.

There are few case reports on the relationship between COVID-19 infection and CML. However, according to the prognosis and the literature reviewed, patients may benefit from the use of TKI.

Acknowledgments

None to declare.

Financial Disclosure

There is no funding for this manuscript.

Conflict of Interest

The authors declare not having conflict of interest in the publication of this article.

Informed Consent

The authors have the informed consent of the patient that it is valid for the publication of this manuscript.

Author Contributions

Zuniga-Perea V. contributed to conceptualization, methology, writing, reviewing, editing and preparation of the original draft. Chazaro-Rocha was responsible for conceptualization, methology, writing, reviewing and editing of the report. Torres-Fierro A. contributed to conceptualization and supervision of the report. Delgado- Lopez N. was responsible for writing, reviewing and editing of the report.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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