To the Editor,
1.
Dasatinib is a second‐generation tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia (ALL) and Ph+ chronic myeloid leukemia (CML). This multi‐kinase inhibitor prevents the proliferation of the leukemic cells [1] but also has potent immunosuppressive effects. Dasatinib exposure results in decreased numbers of B and natural killer (NK) cells [2] and cytomegalovirus (CMV)‐specific CD4+ and CD8+ T‐cell counts [3, 4]; and impaired degranulation and cytokine production, including IL‐2, IFN‐γ, and TNF‐α [2, 5]. Since susceptibility to CMV is highly dependent on CMV‐specific T‐cell responses [6], by inhibiting distinct off‐target kinases in immune effector cells [2, 3, 4, 5], dasatinib exposure may impact predisposition to CMV reactivation.
Several cases of CMV colitis or hepatitis have been reported in dasatinib‐treated patients [7, 8, 9, 10, 11, 12]. Dasatinib is an independent risk factor for CMV reactivation in allogeneic hematopoietic cell transplantation (HCT) recipients [13]. However, scarce data exists regarding the risk of CMV reactivation in dasatinib‐treated non‐HCT populations. In the clinical trial of dasatinib plus blinatumomab for Ph+ ALL, CMV reactivation/infection was one of the most common adverse events occurring in ~10% of the study subjects [14], despite lack of routine monitoring. In a study of patients with Ph+ leukemia with large granular lymphocyte morphology during dasatinib therapy, more than 40% had evidence of CMV reactivation [15].
To further explore the association between dasatinib and risk of CMV in both HCT and non‐HCT patients, we conducted a single‐center retrospective cohort study assessing the rate of CMV reactivation in adult patients with Ph+ ALL who received dasatinib from 2016 to 2024; the control group consisted of 85 adult Philadelphia chromosome‐negative (Ph−) ALL patients, who did not receive TKI. The study was approved by the institutional review board and conducted consistently according to the principles of the Declaration of Helsinki. Institutional protocols for antiviral prophylaxis, CMV PCR monitoring and preemptive therapy are described in Data S1. Primary study outcomes were CMV reactivation (any viremia) and clinically significant CMV (cs‐CMV; CMV viremia or end‐organ disease that required antiviral treatment) [6, 16]. Mann–Whitney U, Fisher's exact, Fine‐Gray or log‐rank tests were used, where appropriate. Time‐to‐event data were censored at 360 days (or loss of follow‐up; and in selected cumulative hazard analyses at time of death or HCT), using the date of leukemia diagnosis as starting point for all the groups. To estimate the probability of CMV in the presence of a competing event (such as death prior to CMV reactivation), the cumulative incidence function (CIF) was used. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated in Cox proportional hazards regression models treating HCT as time‐dependent covariate (and as fixed covariate in supplementary analyses) to account for changes in transplant status and to avoid immortal time bias. Clinically relevant covariates were selected a priori. Model performance was assessed using Schoenfeld residuals, variance inflation factors, C‐index, and AIC. A p‐value of < 0.05 was considered statistically significant. Statistical analyses were performed using R version 4.5.1 and GraphPad Prism version 10.2.2.
A total of 42 dasatinib‐treated Ph+ ALL patients (including three patients with Ph+ CML in blast phase) were identified (Table S1). Dasatinib was started at a median of 7 days (IQR, 3–13) from leukemia diagnosis. All the HCT recipients received dasatinib within the year prior to transplant. Other than treatment era, there were not statistically significant differences in baseline characteristics between dasatinib‐treated and control groups (Table S1).
The median time from dasatinib to CMV reactivation was 186 (138–287) days. Except for one case in a patient with unknown serostatus, all the cases of CMV reactivation occurred in seropositive subjects (Figure S1). The incidence of CMV reactivation (any viremia) was higher in dasatinib‐treated subjects versus control groups, regardless of transplant status (Figures S2 and S3). Among CMV seropositive individuals, the 1‐year incidence of CMV reactivation (any viremia) was higher in dasatinib‐treated patients compared with controls, as follows: 52% versus 12%, p = 0.0001, for the entire cohort; 67% versus 23%, p = 0.004, among HCT; and 24% versus 0%, p = 0.02, for the non‐HCT group (Figure S3). Likewise, the 1‐year incidence of cs‐CMV was significantly higher among dasatinib‐treated versus controls (Figure S3). These associations remained true in CIF analysis with death treated as a competing event (Figure 1), and in time‐to‐event analyses censoring at the time of HCT (Figure S4).
FIGURE 1.
One‐year cumulative incidence of CMV reactivation (any viremia) and clinically significant CMV reactivation in CMV seropositive dasatinib‐treated patients and control groups. Time‐to‐event analyses correspond to cumulative incidence functions. Red lines correspond to dasatinib‐treated subjects; control groups are shown in gray. Top panels correspond to the entire cohort; second row panels correspond to CMV seropositive subjects; third row panels are for HCT group, and forth row for non‐HCT group. Panels on the left are for CMV reactivation (any viremia) and panels on the right are for clinically significant CMV reactivation. The number of patients at risk is shown at the bottom of each panel.
Among CMV seropositive subjects, there was 1 (5%) case of tissue invasive disease in the HCT dasatinib‐treated group, 3 (23%) cases in the non‐HCT dasatinib‐treated group, and none among controls (Figure S1); all the cases of tissue‐invasive disease corresponded to biopsy‐proven CMV colitis.
In Cox proportional hazards regression models adjusting for age, gender, treatment era, primary prophylaxis, CMV serostatus and HCT status, dasatinib remained independently associated with a sevenfold increase in the risk of CMV reactivation (aHR, 7.1; 95% CI, 2.2–23; p = 0.001; Table S2). The association between dasatinib and increased risk of CMV remained true in an extended Cox regression model with HCT as time‐dependent covariate (Table 1).
TABLE 1.
Cox proportional hazards regression for 1‐year risk of CMV reactivation.
| Characteristic | Univariable analysis | Multivariable analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | aHR | 95% CI | p | |
| Dasatinib | 6.7 | 2.7–17 | < 0.001 | 3.4 | 1.1–11 | 0.03 |
| Age | 0.99 | 0.97–1.0 | 0.4 | 1.0 | 0.97–1.0 | > 0.9 |
| Female sex | 2.4 | 1.1–5.5 | 0.04 | 1.1 | 0.4–3.1 | 0.9 |
| Treatment era 2020–2024 | 0.7 | 0.3–1.6 | 0.4 | 2.2 | 0.7–7.2 | 0.2 |
| CMV IgG seropositive | 6.7 | 1.6–29 | 0.01 | 0.5 | 0.1–4.3 | 0.5 |
| HCT a | 91 | 31–274 | < 0.001 | 114 | 21–631 | < 0.001 |
| Primary prophylaxis | 1.9 | 0.9–4.4 | 0.12 | 0.44 | 0.1–1.7 | 0.2 |
Note: Statistically significant p‐values (p < 0.05) are shown in bold.
Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; CMV, cytomegalovirus; HCT, hematopoietic cell transplantation; HR, hazard ratio.
HCT was treated as a time‐dependent covariate in this analysis.
In a seminal report by Marty and colleagues at Dana‐Farber Cancer Institute [13], dasatinib use after HCT in Ph+ ALL significantly increased the risk of CMV reactivation (any viremia) in the first year after HCT in CMV‐seropositive recipients (n = 21), even after adjusting for acute graft‐versus‐host disease (GVHD; aHR: 7.65; 95% CI, 1.84–31.7). In an equally sized cohort of dasatinib‐exposed HCT recipients, our findings confirm the increased risk of CMV reactivation with dasatinib use (for both any viremia and cs‐CMV) in HCT recipients. In addition, we provide novel data for this association in non‐HCT Ph+ ALL patients.
The observed 1‐year incidence of cs‐CMV in the CMV seropositive, dasatinib‐treated, non‐HCT group (24%), was higher than the 11% incidence of cs‐CMV, reported by our group, in CMV seropositive patients undergoing chimeric antigen receptor (CAR) T‐cell therapy [17]. Even more, while the occurrence of tissue‐invasive disease in the HCT cohort (5%) was consistent with the previously reported incidence at our institution [16], the incidence of tissue‐invasive disease among CMV seropositive individuals in the dasatinib‐treated non‐HCT cohort was higher than expected (23%). Therefore, the risk of CMV in seropositive, Ph+ ALL patients receiving dasatinib is comparable to the substantial risk of CMV characteristic of seropositive subjects undergoing transplantation and cellular therapies [16, 17, 18].
Current guidelines from the American Society for Transplantation and Cellular Therapy recommend the use of antiviral prophylaxis for prevention of CMV in allogeneic HCT recipients, and routine monitoring of CMV in CAR‐T recipients. The 2026 NCCN guidelines for prevention and treatment of cancer‐related infections list CMV as an infection concern for patients receiving dasatinib, but do not specify a monitoring protocol for non‐HCT patients. We propose that CMV IgG serology should be obtained in all Ph+ ALL patients treated with dasatinib, and that CMV seropositive subjects should undergo routine monitoring of CMV viremia, resembling the preemptive strategy of HCT. There are caveats to this approach. The optimal frequency of monitoring and the threshold of CMV viremia to initiate antiviral therapy in non‐HCT patients remains to be established. In addition, considering that three of the four patients with biopsy‐proven CMV colitis in the present study had low or no detectable CMV viremia at the time of diagnosis, efforts should be made to obtain colonoscopy for tissue diagnosis; early colonoscopy is important to distinguish between CMV colitis, gastrointestinal GVHD (among HCT recipients), and dasatinib‐induced colitis; the latter, with reported incidence of 18%, typically resolves after discontinuation of dasatinib [8, 19].
Limitations of the present study include its single‐center retrospective design. Yet, to our best knowledge, this is the largest cohort studying CMV events in dasatinib‐treated non‐HCT Ph+ ALL patients. CMV viremia in the non‐HCT cohort was monitored using a sign/symptom‐based screening approach. This introduces the potential for detection bias; however, the testing frequency is unlikely to influence the incidence of tissue‐invasive disease, which was predominant in the dasatinib‐treated non‐HCT group. Quite the reverse, lack of standardized monitoring could have led to episodes of asymptomatic CMV viremia that were overlooked, and it is conceivable that the incidence of CMV in this group was underestimated. The control group consisted of patients with Ph− ALL, which traditionally have better outcomes than Ph+ ALL patients; however, this historical disadvantage has been largely eliminated in the contemporary era with the use of TKI‐immunotherapy combinations with long‐term survival rates of 75%–80% [20]. Therefore, the observed risk of CMV with dasatinib is unlikely to be driven by the underlying ALL type. Finally, four patients had received other TKI prior to dasatinib, and although all the CMV events occurred while receiving dasatinib, it remains unclear whether the association between dasatinib and risk of CMV is drug specific, or rather a class effect toxicity of TKI.
Despite these limitations, we provide preliminary findings that set the foundation for larger prospective studies to further investigate this association. Until more data becomes available, considering the increased risk of CMV associated with dasatinib in this cohort and previous studies [7, 8, 9, 10, 11, 12, 13, 14, 15], CMV preventive strategies should be strongly considered in Ph+ ALL patients receiving dasatinib (and possibly other TKI), regardless of HCT status.
Funding
The authors have nothing to report.
Ethics Statement
This study was reviewed by our Institutional Review Board, the University of Miami Human Subject Research Office, and deemed to be exempt. Data collection was conducted in concordance with all institutional guidelines and procedures.
Consent
Waiver of informed consent was granted due to minimal risk research.
Conflicts of Interest
Jose F. Camargo—Consultancy/speaker: AiCuris, Gilead, GlaxoSmithKline, and Merck. The other authors declare no conflicts of interest.
Supporting information
Figure S1: Study subjects flow chart.
Figure S2: One‐year cumulative incidence of CMV reactivation (any viremia) and clinically significant CMV reactivation in dasatinib‐treated patients and control groups.
Figure S3: One‐year cumulative incidence of CMV reactivation (any viremia) and clinically significant CMV reactivation in CMV seropositive dasatinib‐treated patients and control groups.
Figure S4: One‐year cumulative incidence of CMV reactivation (any viremia) and clinically significant CMV reactivation in dasatinib‐treated patients and control groups.
Data S1: ajh70452‐sup‐0005‐Supinfo.docx.
Table S1: Characteristics of study subjects.
Table S2: Cox proportional hazards regression for 1‐year risk of CMV reactivation.
Acknowledgments
The authors are indebted to all the patients who participated in the study; and to Michele I. Morris, Cara Benjamin, Krishna V. Komanduri, and other members of the Division of Transplantation and Cellular Therapy group for critical support of this work.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Study subjects flow chart.
Figure S2: One‐year cumulative incidence of CMV reactivation (any viremia) and clinically significant CMV reactivation in dasatinib‐treated patients and control groups.
Figure S3: One‐year cumulative incidence of CMV reactivation (any viremia) and clinically significant CMV reactivation in CMV seropositive dasatinib‐treated patients and control groups.
Figure S4: One‐year cumulative incidence of CMV reactivation (any viremia) and clinically significant CMV reactivation in dasatinib‐treated patients and control groups.
Data S1: ajh70452‐sup‐0005‐Supinfo.docx.
Table S1: Characteristics of study subjects.
Table S2: Cox proportional hazards regression for 1‐year risk of CMV reactivation.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.