Introduction

Chronic myeloid leukemia (CML) is a clonal neoplasm of the hematopoietic system, which results from the malignant transformation of the pluripotent stem cell, with the continuous ability to differentiate to all cell lines [1, 2, 3, 4, 5]. According to the contemporary bibliographic references, CML is characterized by the uncontrolled multiplication of myeloid series cells, with the increasing circulating and total granulocyte load, comprises 15 - 20% of all cases of leukemia in adults, being the most common chronic myeloproliferative hemopathy [1, 3, 5, 6, 7, 8, 9]. CML was presumably described and recognized as a distinctive nosological entity by Craigie D. in 1845 [10, 11]. In 1865, the use of arsenic (Fowler's solution) in the treatment of CML was documented. The concept of chronic myeloproliferative neoplasm as a morphological and pathogenetic landmark of CML was introduced by Dameshek in 1951 [12]. CML modbidity increases with age, with a maximum incidence between 45 and 60 years, which indicates the predominant involvement of a workable population [6, 13]. There are the reports in the international periodical literature about the increased susceptibility of patients with malignant neoplasms to SARS-CoV-2 infection and its increased incidence (1% [95% IU, 0.6, 1.7%] as compared to the apparently healthy population (0.1% [0, 0.12%]), but these estimations are controversial, and the contagion risk is not determined in regards to the type of hematological malignancy [14, 15, 16]. The increased incidence rates in the working-age population, commonly late diagnosis of CML in the current epidemiological context and the significant level of disability in advanced stages of the disease can be considered as major topics of hematooncology and public health, which argued the need to study its epidemiological and managerial-diagnostic aspects.

The aim of the study was the comparative evaluation of the current epidemiological patterns and the contemporary diagnostics output in CML, axed on the optimization of tactics of diagnosis management in the context of the pandemic with COVID-19 infection.

Material and methods

An analytical, qualitative, secondary study was performed – the narrative review of literature in the form of a synthesis article. The article summarized and systematized various primary studies, dedicated to the epidemiological and diagnostic aspects of CML. The accumulation of information for this research was accomplished by analyzing data from the specialized international bibliographic sources and official statistics on the respective malignant myeloproliferative neoplasm. In order to achieve the formulated aim, the scientific medical publications were searched over the GoogleSearch, PubMed, Z-library, NCIB, Medscape, Hinari database, by the keywords: “chronic myeloid leukemia”, “incidence”, “prevalence” , “mortality”, “survival”, “management”, “diagnosis”, “COVID-19”. More than 70 bibliographic sources of reference have been studied. Fifty three relevant primary sources were identified and selected, according to the significance of the impact score, with the scientific, reproducible and transparent approach to the subject under discussion, with the subsequent data extraction and analysis. Intending to minimize errors, a copy of the data extraction sheet was initially produced, listing all the elements to be extracted from the primary studies [17]. In order to diversify the conclusions, the results of foreign studies were supplemented by the published research data from the Republic of Moldova. Carrying out a qualitative research, the narrative synthesis of data was undertaken. 

The updates and milestones regarding the diagnosis of CML were studied in the light of the following aspects:

• incidence and mortality by CML in regard of the geographical area and the level of the social-demographic index (SDI);

• the global burden of the disease (GBD);

• the exposure of CML patients to the risk of SARS-CoV2 infection;

• the output of morphological, immunological, cytogenetic and molecular investigations in the diagnostic management of CML.

The practical importance of the study lies in highlighting the priority diagnosis aspects of CML, assessing the risk of infection of CML patients with SARS-CoV2 and reducing the negative effects of the COVID-19 pandemic on the management of CML.

Results and discussions

The epidemiological and management issues of CML are related ambiguously by the international bibliographic references and continue to stimulate both scientific and practical interest. The data from summarized epidemiological studies attest to the detection of CML at any age, with an average of 50 years at the time of diagnosis. The results of the published studies show that approximately 2.5% of cases with CML are attributed to the age group under 20 years [18], 7.4% - to the age group between 20 - 34 years and 33% - to the age groups under 40 years, which denotes the ponderable rate of young patients [6, 13, 19]. The incidence of CML varies between 0.8 - 2.0 cases per 100000 population. The National Institutes of Health estimated the number of cases diagnosed de novo in the United States at 8950 and the number of deaths from this disease at 1080 in 2017. The total number of patients diagnosed with CML increased annually by 2% during 2007-2016, and the total number of deaths decreased annually by 1% during the years 2008-2017 [20]. The 5-year survival rate years increased from 22% in the mid-70s to 90% currently in patients undergoing continuous chemotherapy with 1st generation tyrosine kinase inhibitors [21]. CML predominantly affects males, the male:female ratio being 1.3-1.7:1. The study of the development of CML according to age category argued the distinction between juvenile and adult forms of the disease.

Globally, in 2016 leukemias caused 10.2 million DALYs (disability-adjusted life-years), exceeding the respective index for malignant lymphomas (6.8 million DALYs) [22]. It is worth of considertation the study of the global burden of disease in 2017, which analyzed and systematized data on the incidence and annual mortality of CML, DALYs, risk attributive factors, as well as information on age, geographical distribution and sex. The GBD 2017 study divided the countries of the world into five quintiles of SDI. Five  quintiles of SDI (high, high-medium, medium, low-medium, low) and 21 geographical regions have been identified. With regard to CML, the GBD has varied significantly from country to country due to different possibilities for early screening, accessibility of new antineoplastic agents and medical resources [23, 24]. In order to describe the CML burden, annual incidence cases, death cases, DALYs and the corresponding age-standardized rate (ASR) were analyzed. The estimated annual percentage changes (EAPC) were calculated on the ASR base and used to quantify the ASR trend. In 1990, the age-standardized incidence rate (ASIR) was higher (1.34 per 100000 population) in quintiles with high SDI. By 2017, there was a dramatic upward trend of ASIR in low SDI quintiles (0.65 per 100000 population, 95% IU), which exceeded high SDI quintiles (0.53 per 100000 population, 95% IU). Regarding the geographical distribution, in 2017 Western Europe with an incidence of 61.62 x 102 (95% IU) of cases and South Asia with an incidence of 80.44 x 102 (95% IU) of cases remained in the top of the higher incidences among regions of the world. In the same year in these geographical areas the highest number of deaths and DALYs was found - respectively 42.45 x 102 (95% IU) and 66.60 x 102 (95% IU), 68.46 x 103 (95% IU) and 207.79 x 103 (95% IU). In 1990 the age-standardized death rate (ASDR) (0.92 per 100000, 95% IU) and the ASR of DALYs (24.23 per 100000, 95% IU) proved to be superior in quintiles with high SDI. In 2017, the situation was diametrically opposed, with a comparatively high level of ASDR (0.6 per 100000 population, 95% IU) and ASR of DALYs (16.71 per 100000 population, 95% IU) in quintiles with low SDI. The study found that ASIR (ρ = - 0.610, p <0.01), ASDR (ρ = - 0.471, p <0.01) and age-standardized DALYs rate (ρ = - 0.403, p <0.01) ) in 1990 manifested negative correlation with the corresponding EAPC. The correlations between SDI and EAPC incidence (ρ = - 0.509, p <0.01), deaths (ρ = - 0.620, p <0.01) and DALYs (ρ = -0.632, p<0.01) were also considerably negative. Herewith, the the referring study could demonstrate a faster decreasing trend of ASR in countries with bulkier disease reservoir baseline in 1990 or with higher SDI in 2017. Therefore, the trends in the CML burden revealed by the GBD study provided important information for the promotion of medical services and public health. Despite the declining overall trend of ASIR, ASDR, and age-standardized DALYs in quintiles with high SDI, the CML burden remains stable due to increased population growth in developing countries and an aging population in developed countries [22]. Between 1990-2017, the incidence decreased by 34.9% in quintiles with high SDI, increasing by over 60% in quintiles with low SDI, medium-small and medium SDI. Developing countries, thus, continue to bear the heavy burden of CML  dute to contribution of their reduced access to treatment with TKIs [25]. It is summarized about the relationship between the epidemiological trends of CML with age and gender, which has an impact on policy-makers [23]. Aging, directly proportional to the reduction of hematopoietic stem cell function, is considered an essential factor associated with leukemogenesis [26, 27]. The survival of patients with CML is age-related, which serves as a key factor in the selection of treatment options [28,29]. Quintiles with higher SDI and an aging population showed a more significant proportion of patients over 70 years of age. Males formed a higher risk group for developing CML as compared to females, and the male:female ratio ranged from 1.2 to 1.7 [30, 31]. It is evoked, such as higher overall survival, the hormonal status of females, genetic and environmental factors could have an impact on the age distribution of patients with CML [32, 33]. At the same time, in quintiles with low SDI, the ASDR and DALYs in women exceeded the respective indicators in males in 2017. Epidemiological studies found in females from the low-income countries a tendency of mortality increase due to the inadequate early screening and treatment [24, 32, 33].

In the current epidemiological context, the association of COVID-19 infection with CML is of both scientific and practical interest, taken into account an apparently immunocompromised status of patients with this myeloproliferative neoplasm. The epidemiological and evolution aspects of COVID-19 infection in patients with CML are reflected controversially in the contemporary international literature [34].

According to the results of the CANDID multicenter study, 110 cases of CML from 20 countries were reported to iCMLf (International Chronic Myeloid Leukemia Foundation), especially from European - 61%, Asians - 15%, South Americans - 12%, North Americans - 10%, African - 2% and Oceanic - 1%. Forty-six haematologists reported only 91 (0.7%) cases of COVID-19 infection in 12236 patients with CML under their supervision, which may suggest that immune status in chronic phase of CML is not a contributing factor in the development of this severe viral disease [35]. The age of patients diagnosed with COVID-19 ranged from 18 to 89 years, with a mean age of 54, which exceeded the mean age in the total CML population reported in the majority of studies [5, 6, 36]. The mean time from confirmation of CML diagnosis to the development of COVID-10 infection was 7 years, with the limits ranging between 0.5-25 years.

The authors reported that of all infected patients, 77 (70%) received standard chemotherapy with TKIs, 33 (30%) discontinued it during the diagnosis and treatment of the infection, and 18 (16%) were not treated with chemotherapy due to different reasons. COVID-19 infection progressed asymptomatically in 8 (7%) cases, in mild form without hospitalization - in 49 (45%), medium with hospitalization - in 19 (17%), severe with treatment in intensive care units - in 19 (17%), being of indeterminated severity in 15 (14%) cases. Death from COVID-19 was found in 12 (10.9%) patients. The survival was analyzed according to sex, age, chemotherapy protocol, comorbidities, anti-COVID-19 treatment and level of economic development of the country. Univariate analysis showed a higher mortality rate in patients aged ≥ 75 years (60% vs 7% in those under 75 years, p<0.001), severe form of infection (63% vs 0% in non-severe forms, p < 0.001) and in patients over 75 years of age treated with generation 1 TKIs (25% vs 3% against the background of 2nd generation TKIs vs 0% in those without therapy with TKIs, p = 0.003).

Another study of 125 hospitalized patients with malignant haematological neoplasms revealed a 10 percentile rate (6, 17%) of COVID-19 infection, but none of the subjects were diagnosed with CML [15] . Despite the results of this study in the same year during the pandemic with SARS-CoV-2 infection, 530 cases of CML were studied in 29 medical centers of the Anti-Cancer Association of Hubei (China) [37]. Five patients developed COVID-19 infection, so the prevalence of this disease was 0.9% (95%, 0.1, 1.8% privacy interval), nine times exceeding that indicator (0,1% (0, 0,12%)) in the healthy population, but being lower than 10% (6, 17%) reported in the hospitalized patients with other malignant hematological neoplasms and 7% (4, 12%) - in the healthy health care providers. The evolution of the infectious process in cases with CML has proven to be typical both in terms of the clinical picture and the imaging of the chest on computed tomography. Co-variations associated with an increased risk of developing COVID-19 among patients with CML were exposure to persons infected with SARS-CoV-2 (P = 0.037), lack of complete hematologic response (P = 0.003) and comorbidities (P = 0.024). At the same time, the increased risk of developing COVID-19 infection was observed in patients with advanced CML (P = 0.004) despite obtaining a complete cytogenetic response or major molecular response at the time of exposure to SARS-CoV-2. During the treatment with TKYs, COVID-19 infection developed in one of 21 patients under the 3rd generation medication, in 3 of 346 under the imatinib mesylate medication, and in none of the 162 who received the 2nd generation (P = 0.096). From these data it can be suggested that generations 1 and 2 of TKIs are associated with a reduced risk of COVID-19 infection, which disapproves the corresponding evaluations from the previous study. Other co-variations such as age and duration of treatment with TKIs were not associated with an increased risk of developing COVID-19 infection. It can be recapitulated that patients with identified risk factors should benefit under the management plan from the increased surveillance in terms of SARS-CoV-2 infection, with the possibility of protective isolation and testing.

In the majority of contemporary bibliographic sources, published studies, based on representative batches of cases there are identified and registered all 3 clinical-evolutionary stages of CML: chronic (early and late) , acceleration and acute [1, 2, 3, 18, 38, 39, 40].

According to the results of a study from the Russian Federation, of 5655 patients enrolled in the CML register, the vast majority (93.1%) were diagnosed in the chronic phase, only 6.4% - in the acceleration phase and minor number (0,4%) – in the blast crisis. The mentioned percentage distribution of CML patients by phases is comparable with the results of other international researches, as well as local ones (chronic phase - 92.3%, acceleration - 7.7%) in the field of chronic myeloproliferative neoplasms [8, 18, 21, 40]. The data of the bibliographic references allow to summarize about the improvements in the diagnostic approach to the late chronic phase, with the systematization and grouping of clinical symptoms, the results of investigations and highlighting 4 syndromes in most patients: tumor intoxication, tumor proliferation (hepato- and splenomegaly), anemic and thrombotic-hemorrhagic complications [19]. The diagnosis is difficult to establish in reasonable terms in 15-30% of cases with asymptomatic evolution of the late chronic phase. At the same time, it is reported about the association of the late chronic phase with complications caused by hyperleuko- and thrombocytosis (spleen infarction, retinal edema, retinal microthrombosis, microthrombosis in the corpus cavernosum, stupor, ovarian apoplexy, neuro-sensory disorders, etc.) [41, 42, 43]. The average survival of patients without specific treatment is 3-5 years in the chronic phase, and 1-2 years in the acceleration phase [9]. It may be considered of practical interest a clinical-evolutionary aspect of transformation of the late chronic phase into a blastic crisis in 20% of patients without the development of the acceleration phase, which requires a radical change in therapeutic management tactics. According to contemporary conceptions and classifications, hepato- and splenomegaly are not considered as criteria for transforming CML in advanced stages [1, 19]. The clinical-hematological picture in the acute phase corresponds to the clinical-hematological picture of acute leukemia, with infectious and hemorrhagic complications, manifesting itself in regard to the morphological type and immunophenotypic spectrum of the blast crisis: myeloid (50-80%), lymphoid (20-30 %) or undifferentiated (≤ 25%). The average survival of patients with the acute phase varies between 3-6 months, being associated with a insignificantly less unfavorable immunocompromised status and prognosis in the lymphoblastic crisis, which argues the major importance of early diagnosis of CML, especially in the current epidemiological context.

According to contemporary clinical guidelines and recommendations, morphological, cytogenetic (standard, FISH) and molecular-genetic examinations of peripheral blood and bone marrow have become indispensable steps of diagnostic management regardless of the clinical-evolutionary phase of CML [19, 43]. Morphocytochemical analyzes (reactions for myeloperoxidase, lipids, PAS, α-naphthylesterase), immunophenotyping of leukemic cells (with a score of a phenotype indicator ≥ 1) are practicable and resultant in the advanced stages. Therefore, the expression of the phenotype CD13, CD33, CD34, CD117 is found in blast cells in the myeloblastic crisis [9]. The acute B-cell lymphoblastic phase is usually confirmed by the expression of the immunophenotype CD19, CD20, CD22. The immunophenotype CD5, CD8, CD10 assesses the T-lymphoblastic crisis. According to the Recommendations of the European Group (EuroFlow Group) for Immunological Classification of Acute Leukemias the summary score over 2 points is necessary for the determination of the cell line [44]. Blast cell clusters are seen in the medullary aspirate, which exceed 20%. Fragments of megakaryocyte nuclei and erythrocaryocytes are detected in the peripheral blood. In some cases the acute phase evolves in the form of sarcomatization, affecting the lymph nodes, bones, other organs.

It should be noted that CML was the first malignant neoplasm identified in association with chromosomal aberration [13]. In 1960, USA scientists G. Nowell and D. Hungerford detected translocation t(9;22)(q34;q11) in bone marrow cells in CML patients, named as the Philadelphia chromosome (Ph-chromosome) [4], which is formed as a result of mutual translocation between the long arms of chromosomes 9 and 22. It is distinguishable in all dividing medullary cell lines. This chromosomal aberration is the cytogenetic marker of CML, ensures a definitive diagnosis and, according to studies published in the international periodical literature, has to be determined by conventional cytogenetic examination or FISH during patient follow-up for objective evaluation of cytogenetic response to the treatment with TKIs [6,39,48 ]. In published studies, the rate of Ph-chromosome-positive bone marrow cells ranged from 20 to 100% [13, 18]. In the absolute majority of cases (72.7%) Ph-chromosome was detected in over 70% of bone marrow cellular elements and could ensure a quick and reliable diagnosis. Beyond simple mutual translocation between chromosomes 9 and 22, approximately 5-10% of CML cases may have other types of Ph-translocations. These simple types involve one or more chromosomes in addition to 9 and 22, with chromosome 22 always changing. Secondary changes or other complex cryptic chromosomal rearrangements in BCR-ABL1 can be observed in 9-16% of patients with CML [45, 46]. At the same time, 30-50% of chromosomal types in CML represent fused genes that can be detected only by molecular techniques such as FISH or polymerase chain reaction (PCR) [47]. It is worth noting that the clonal evolution of CML with the transformation of the chronic phase into the acceleration phase may be associated with the appearance of additional chromosomal aberrations, especially trisomia 8, isochromosome 17 and Ph-chromosome duplicate [9]. These cytogenetic aberrations are considered as diagnostic criteria for the acceleration phase and should be applied in the differential diagnosis with chronic phase and acute leukemia.

Identification of the chimeric BCR-ABL fusion gene and transcripts p210, p190 and p230 with tyrosine kinase activity profiles CML at the molecular level. Due to the formation of the BCR-ABL1 fusion oncogene, the tyrosine kinase activity of the ABL1 portion increases, serving as a trigger-factor of the malignant transformation of the phenotype. The breakpoint is inserted in the BCR oncogene, which generates the translocation t(9;22)(q34;q11) in CML and involves the e12-e16 exons (known as b1-b5) in the major region (M-bcr). The p210 protein - the major transcription product (M-bcr) - is found in most patients with CML, being responsible for the classic CML phenotype. The p190 protein is formed following the rearrangement of m-bcr region, reflects the production of e1a2 transcript. It is less frequently determined in CML and denotes an unfavorable evolution of the disease, commonly with resistance to chemotherapy. The transcription product p230 is rarely identified in μ-bcr region, being associated with slow disease progression. Oncogenic BCR-ABL acts by mitogenic signaling, influences proteosome-mediated degradation, altering the signal transmission cascade and constantly keeping cell growth active. Leukemic cells proliferate, with gradual expansion into the medullary cavities and reduction of the clone of normal hematopoietic cells, what may be precisely determined as a percentage by combining the cytomorphological examination, FISH and RT-PCR of the medullary aspirate. 

In addition to fast diagnosis, FISH and PCR are able to detect rare BCR-ABL gene variants and breakpoints that go unnoticed by conventional cytogenetics, with higher specificity and sensitivity. These techniques are more sensitive and important not only for the diagnosis and evaluation of the response to treatment, but also for the differentiation from other chronic myeloproliferative neoplasms. The authors summarize that FISH is recommended for diagnosis in cases where the Ph-chromosome is not detectable by classical cytogenetics. Techniques such as quantitative real-time PCR (RQ-PCR) or reverse transcription PCR (RT-PCR) serve as methods of choice for both accurate diagnosis and determination of minimal residual disease after bone marrow transplantation due to their superior sensitivity, allowing early diagnosis of the disease relapse and being more effective in determining the response to treatment as compared to classical methods [49]. If the bone marrow cells cannot be obtained, cytogenetic examination of the banded chromosomes can be substituted by FISH blood cell interphase, using dual color fusion probes that allow the detection of BCR-ABL+ nuclei. Banded chromosome analysis is required to detect additional chromosomal abnormalities.

FISH may become mandatory in determining translocation variants [50]. Qualitative RT-PCR is performed on RNA extracted from the bone marrow or freshly collected blood cells. The type of transcription is identified, either e14a2 or 13a2 (also known as b3a2 and b2a2), and less often e19a2 or e1a2, indicating the weight of the BCR-ABL protein (p210, less often p230 or p190). By RT-PCR analysis of quantitative determination of the chimeric BCR-ABL p210 gene in blood cells, the published studies highlight its large variations: 21.84 - 100% IS [5, 36, 40, 51]. Multiplex PCR, as a rule, detects the transcription product in the major region (M-bcr). The analyzed studies reveal that in most cases (69.8%) the expression of BCR-ABL chimeric gene transcripts is identified in over 65% of bone marrow cellular elements [48]. One study mentions a phenomenal aspect of molecular diagnosis, as RT-PCR with a sensitivity of 10-8 identifies BCR-ABL1 chimerism in 25-30% of apparently healthy adults [9]. It is hypothesized that BCR-ABL1 may not be the only genetic aberration required for the development of CML. Abnormal expression of JunB, a component of the activator of the protein 1 family of transcription factors, may have an impact on the pathogenesis of CML due to modulating the initiation, progression, and maintenance of the myeloid differentiation program [52]. Nevertheless, it is recapitulated that real time RT-Q-PCR is not the first-line diagnostic option and may be required for monitoring the response to treatment [39, 53]. These are recommendations for arranging the diagnosis management.

Conclusions

1. CML is characterized by the involvement of the workable age categories, aggressive evolution in advanced phases, with considerably low survival, an immunocompromised status and more frequent contamination by COVID-19 infection, which indicates the major importance of early diagnosis.

2. Despite the declining overall trend of ASIR, ASDR and age-standardized DALYs at the expense of high SDI quintiles, the CML burden remains stable due to the growing population in developing countries and the aging population in developed countries.

3. The mortality rate in cases of CML associated with COVID-19 infection is higher in patients ≥ 75 years of age, advanced CML phases, severe form of infection and in those over 75 years of age treated with 1st generation TKIs.

4. Management of patients with primary diagnosed CML, with high risk factors, should include enhanced surveillance for SARS-CoV-2 infection, with the possibility of protective isolation and testing for COVID-19 infection in order to develop personalized target chemotherapy tactics and optimal selection of the generation of TKIs.

5. Diagnostic management of patients with CML includes morphological, cytogenetic and molecular-genetic investigations of the peripheral blood and bone marrow regardless of the phase of clinical evolution, with FISH and RT-PCR as proving resolutive modalities.

6. FISH is recommended to be included in the diagnostics management pathway of patients in cases where the classical cytogenetic examination does not detect Ph-chromosome or additional chromosomal aberrations, especially in the acceleration and acute phases of CML.

Competing interests

None declared

Author’s ORCID ID: 

Vasile Musteață - https://orcid.org/0000-0002-9471-7170

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