Viral Infections and Incidence of Reactivations in Chronic Myeloid Leukemia Patients

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, which is identified by the overgrowth of myeloid cells and an accumulation of mature granulocytic cells in the bone marrow, leading to an augmented presence of granulocytes and their progenitors in the peripheral blood [1, 2]. CML can be classified into three phases: chronic phase (CP), accelerated phase (AP), and blast phase (BP). The majority (90–95%) of patients are initially diagnosed in the CP (CML-CP) [3]. As many as 40% of patients with CML may present with no symptoms. People who have symptoms rarely present with issues such as fatigue, weight loss, profuse sweating, abdominal distension, and episodes of bleeding because of platelet dysfunction [4, 5]. A reciprocal translocation causes the fusion of the ABL1 gene from chromosome 9 to breakpoint cluster region (BCR) gene on chromosome 22. This is the hallmark of the CML disease which results in the BCR-ABL1 fusion responsible for abnormal tyrosine kinase activity and its subsequent role in unregulated cell proliferation [6‒8]. CML accounts for 15–20% of adults. In 2018, the worldwide occurrence rate of CML was 1–2 cases per 100,000 adults, constituting roughly 15% of newly identified cases of leukemia in adults [3].

Viral infections continue to be a severe problem in patients with hematological malignancies, especially in those receiving allogeneic stem cell transplants, and they usually result from the reactivation of latent infections [9, 10]. Infections affect morbidity and medication adherence, increasing the risk of treatment failure and complicating the treatment approach [11, 12]. Differences in the incidence and outcome of viral infections among patients with hematological malignancies depend on the intensity and duration of T-cell-mediated immune suppression. Additionally, the type of hematological malignancies, either lymphoid or myeloid, might be a risk factor for viral reactivation. For example, the risk of cytomegalovirus (CMV) and HSV reactivation is higher in patients with lymphoid malignancy, especially chronic lymphocytic leukemia [13].

The use of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of CML as it is highly successful and has transformed the prognosis of patients with CML [14‒16]. However, the use increases the risk of different types of infections in patients with CML, including viral infections [16]. The exact mechanism of TKI-related infection is not well understood, but it is most likely related to their immunosuppressive effects. TKI impairs B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling. Furthermore, TKI might affect cellular immune response, through the effect of T-cell function [17]. The effect of CML on the risk of viral infections is not well described in the literature. This review highlights the risk of viral infections in patients with CML.

We have performed a literature search for English language articles using PubMed, Scopus, and Google Scholar, for the period 2001–2022 (shown in Fig. 1). The selected articles encompass case reports, case series, and informative reviews. The search utilized terms such as “CML,” “Chronic Myelogenous Leukemia,” “Viral,” “Infection,” and “Reactivation.” Records deemed ineligible by automated tools included those published outside the specified range (2001–2022); the year imatinib was approved for CML treatment after interferon treatment failure, studies involving animals, non-English articles, cases involving individuals under 18 years of age, and preprints. Subsequent screening based on title, abstract, and full article review was conducted according to the defined exclusion criteria below. This process led to the final inclusion of 18 articles, involving a total of 41 patients.

The titles and abstracts of the records were screened by two independent reviewers in an independent manner. We examined pertinent articles in-depth for this review. Inter-rater disagreements were resolved following a discussion between the reviewers.

The information extracted by the two reviewers included several factors such as the publication year, age and sex of the patients, the phase of CML diagnosis, the type, presentation, and treatment of viral infection, the CBC indices at the time of diagnosis, the CML treatment and outcome, the length of follow-up, and the final outcome. Significantly missed data were not included in the review.

• 1.

  Patients 18 years or older who are diagnosed with CML.

• 2.

  Patients who are diagnosed with acute viral infections or reactivations after the diagnosis of CML.

Articles include case reports, case series, informative reviews, and clinical trials. The keywords were “CML, Chronic Myelogenous Leukemia, Viral, Infection, Reactivation.” We initially reviewed search results by title and abstract, and articles were selected for more in-depth analysis if deemed relevant. Pertinent articles were examined in-depth for this review.

• 1.

  Patients younger than 18 years.

• 2.

  Patients with a history of bone marrow transplant.

• 3.

  Patients with COVID-19.

• 4.

  Chronic viral infections with human immunodeficiency virus.

In an analysis of 41 patients, with 25 males and 16 females, M:F ratio of 1.6:1, and a median age of 50 ranged from 22 to 79 years (shown in Tables 1 and 2). Most patients with reported viral infections or reactivations were in the CP of CML, with 22 patients (76% of reported cases) in the CP, 6 patients (21%) in the AP, and 1 patient (3%) in the BP (shown in Table 3 and Fig. 2). The increased patient number within the CP aids in comprehending the viral infection and reactivation risk among this patient cohort, without the evidence of overt immunocompromised state commonly seen in patients during the accelerated or BPs of the disease.

Most cases with reported outcomes responded to treatment; only one had a refractory disease; on the other end, 8 cases (32% of reported cases) had a major molecular response, defined as 0.1 percent of baseline BCR::ABL1/ABL1 or ≥3 log reduction. TKIs were used in 40 patients; imatinib was the most used TKI in 31 patients (76%), dasatinib in 8 patients (20%), nilotinib in 1 patient, and 1 patient was treated with interferon (shown in Table 3 and Fig. 3).

The most commonly reported viral reactivations were varicella zoster virus (VZV) in 17 patients (41%) [18, 19], followed by hepatitis B virus (HBV) in 15 patients (37%) [20‒27], other viral reactivations and/or acute infections include CMV in 3 patients [28‒30], Epstein-Barr virus in 2 patients [31, 32], and 1 patient with each John Cunningham polyomavirus [33], human herpesvirus-8 [34], parvovirus B19 virus/human herpesvirus-6 [28], and dengue virus [35] (shown in Table 4 and Fig. 4). This constitutes a restricted patient sample, monitored for a limited period, with cases documented specifically for viral infection or reactivation status. Therefore, it is inappropriate to draw conclusions from this response rate or to compare it with established response rates [36].

The risk of viral reactivations is high in patients with hematological malignancies, especially those receiving allogeneic hematopoietic stem cell transplants [7]. Patients with a diagnosis of CML have a high risk for viral infections and reactivations of latent viruses like VZV and HBV, which is mainly because of the disease itself [34]. Adaptive and innate immune responses are dysfunctional in CP CML patients before progression to overt immune deficiency secondary to blast transformation as evident by the large number of patients having viral reactivation in the CP. CML patients were found to have dysfunctional CD8+ cytotoxic T cells (CTLs) [37]. It was also demonstrated that programmed cell death protein 1(PD-1) which is an inhibitor of both adaptive and innate immune responses is highly expressed on CD8+ T cells in patients with CML [38]. Of note, high PD-1 expression is also maintained in persistent hepatitis C virus infection, contributing to chronic viral infection [39].

On the other hand, treatment by TKI can increase this risk of viral reactivation; therapy with imatinib was associated with significant reductions in immunoglobulin M memory B cells. A study showed that TKI, particularly second-generation TKIs with greater off-target kinase inhibition, inhibited B-lymphocyte functioning and the antibody response to different types of infections [17]. Furthermore, one study analyzing the effects of imatinib on antiviral immune responses showed inadequate protection against viral reinfections as illustrated by the reduced secondary expansion of lymphocytic choriomeningitis virus specific memory CTLs [40]. In another study, a significant suppressive influence of nilotinib on the CD8+ T lymphocyte function was observed [41].

A retrospective study by Mattiuzzi et al. [19] included 771 patients with CML treated with imatinib mesylate and showed that VZV infection is more common in patients with a longer duration of disease. Furthermore, no case of disseminated VZV was found, and overall VZV infection responded well to therapy. Notably, the incidence of VZV infection is much lower in patients on hydroxyurea or interferon therapy. One significant and well-reported viral reactivation in patients receiving TKI therapy is HBV reactivation, with suggestions to check for HBV serology before starting TKI therapy and start prophylaxis in case of positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) [42].On the other hand, hepatitis C infections have not been reported in patients with CML. Prolonged diarrhea in CML patients receiving dasatinib for either the CP or BP should be closely monitored as it may be an indication of CMV colitis [30].

Our review aims at better understanding of the reactivation of latent and acute viral infections in patients with CML, discusses the need for screening and prophylaxis for latent viral infections, and shines a light on an important topic that may affect the morbidity and mortality of patients with CML.

Most patients in the review were in the CP of CML, with 22 patients (76%) in the CP and 6 patients (21%) in the AP; this group is the one we want to focus on; this is because patients in BP are in overt immune deficiency and are more prone for viral reactivations, yet patients with chronic or AP continue to be at risk as described above.

Imatinib was the most commonly used TKI in 31 patients (77.5%), dasatinib in 8 patients (20%), nilotinib in 1 patient, and 1 patient was treated with interferon; this can be explained by the fact that most patients are in the CP, and consistent with the national comprehensive cancer network (NCCN) guidelines, imatinib continues to be the first-line TKI in the CP, primarily in low-risk patients.

The most reported viral reactivations were VZV in 17 cases (41%), followed by HBV in 15 cases (37%). Other viral reactivations include CMV in 3 patients, Epstein-Barr virus in 2 patients, and 1 patient with each John Cunningham polyomavirus, HHV-8, parvovirus B19/human herpesvirus-6, and dengue virus; this reflects the importance of VZV and HBV serology testing before starting TKI and to consider prophylaxis as appropriate.

The main limitation of our review is that the patients’ data were mainly obtained from case reports and series, so the long-term outcomes for those patients could not be appropriately assessed. Also, the number of included cases is limited due to the rarity of viral reactivations in patients with CML who did not undergo stem cell transplantation. Lastly, there was some missing relevant data in those case reports which restricted our review.

This review shows the risk of viral infections and reactivations in the setting of CML disease. Nonetheless, most documented cases with reactivation of the HBV came from East Asian nations such as China, Taiwan, Japan, and Korea. While this could be attributed to the increased prevalence of HBV in these countries, this finding also raises concerns about the degree to which these findings can be generalized to patients in other parts of the world. Additionally, this review highlights the importance of having HBV serology and possibly VZV serology checked before starting TKI therapy, close monitoring for viral reactivations, and a low threshold to suspect viral infections or reactivations in patients with CML. Further studies are needed to assess the need for viral prophylaxis for latent viruses in CML patients after starting TKI and to help in establishing future guidelines.

Not applicable.

The authors have no conflicts of interest to declare.

The publication of this article was funded by Qatar National Library.

Mahmood B. Aldapt and Abdulrahman F. Al-Mashdali: methodology, validation, writing – original draft, writing – review and editing. The first two authors contributed equally. Khaldun Obeidat: data collection, methodology. Prem Chandra: methodology, data Analysis. Mohamed Yassin: supervision. All authors have read and agreed to the published version of the manuscript.