Summary
Infectious complications after high‐dose therapy and autologous stem cell transplantation (HDT‐ASCT) for lymphoma are the leading cause of late non‐relapse mortality. Characterizing the risk of infectious complications over time is important for rational follow‐up and because alternatives to HDT‐ASCT exist for some patients. This national cohort study investigated the risk of severe (defined by requiring hospitalization) late infections after 90 days among HDT‐ASCT‐treated patients with lymphoma in remission relative to the Danish background population (comparators) matched on age, sex and comorbidity score. Anti‐cancer treatment after HDT‐ASCT and death were competing events. This study included 781 patients and 3905 comparators. With a median follow‐up of 7.7 years for patients, the incidence rate ratios of severe infections from 90 days until 2 years after HDT‐ASCT was 8.43 (95% confidence interval (CI): 6.98–10.16) and the 2‐year cumulative risk was 23.7% (95% CI: 20.7%–26.7%) for patients and 3.4% (95% CI: 2.9%–4.0%) for comparators. The risk of severe infections remained increased for up to 10 years after HDT‐ASCT. Respiratory tract infections were the most frequent type, with a 2‐year cumulative risk difference of 10.9% (95% CI: 8.6%–13.3%). Patients were more likely to be prescribed anti‐infectives, including broad‐spectrum antibiotics 5–10 years after HDT‐ASCT.
Keywords: epidemiology, infection, late effects, lymphomas, stem cell transplantation
BACKGROUND AND SIGNIFICANCE
High‐dose therapy followed by autologous stem cell transplantation (HDT‐ASCT) is the standard treatment for fit patients with late relapse of diffuse large B‐cell lymphoma (DLBCL) (beyond 12 months of first‐line chemoimmunotherapy) or Hodgkin lymphoma (HL). 1 , 2 , 3 It is also a commonly used consolidation strategy in first line for fit patients with peripheral T‐cell lymphoma (PTCL), early relapsed follicular lymphoma (FL) and mantle cell lymphoma (MCL). 4 HDT‐ASCT leads to immediate and severe neutropenia with an associated increased risk of bacterial, fungal and viral infection. 5 , 6 , 7 , 8 , 9 Infections are the leading cause of non‐relapse mortality after 100 days (1%–4%), and according to the Center for International Blood and Marrow Transplant Research (CIBMTR), at least 21% of deaths within the first 100 days after HDT‐ASCT are related to infections. 10 , 11 , 12 , 13 However, the risk of late infections after the early period of neutropenia is not well characterized, and the incidence of infections relative to the background population is not studied in a population‐based setting except for MCL. 14 Infectious complications are a surrogate measure of the long‐term impact of HDT‐ASCT on immune function, and delineating risk over time is relevant for patient management in the post‐HDT‐ASCT setting. Furthermore, chimeric antigen receptor T‐cell receptor therapy (CAR‐T) is an effective alternative for a subgroup of patients with early relapse of DLBCL, which historically has been treated with HDT‐ASCT. 15 , 16 , 17 , 18 The use of CAR‐T is expected to increase further in the coming years with new indications and use in earlier lines. CAR‐T is associated with immunotoxicities, including grade ≥3 neutropenia in 10%–12.5% of patients after ≥90 days and late infections, especially of the respiratory tract. 19 , 20 , 21 , 22 , 23 Persisting CAR T cells cause B‐cell depletion and hypogammaglobulinaemia, which also increase the risk of infections. Understanding the long‐term immune dysfunction after HDT‐ASCT is important for the overall benefit/risk assessment of HDT‐ASCT against CAR‐T therapy. The present nationwide study investigated the risk of infections >90 days after HDT‐ASCT relative to a matched background population.
METHODS
This retrospective cohort study was based on national Danish health registries linked using the unique personal identification number. 24 , 25 Patients were identified using the Danish National Lymphoma Registry, which contains information on lymphoma patients diagnosed in haematology departments in Denmark. 26 Inclusion criteria for patients were ≥18 years at first lymphoma diagnosis; received HDT‐ASCT from 2000 to 2017 in the first‐ or second‐line setting for DLBCL, HL, MCL, FL or PTCL; alive without relapse 90 days after the date of stem cell infusion (defined as the index date); and no CNS involvement. Persons with a history of solid organ transplant, HIV or primary immunodeficiencies were excluded (Table S1). 27 Each patient with lymphoma was matched randomly to five persons from the Danish background population (comparators) on sex, age (birth year) and Charlson Comorbidity Index (CCI) score. CCI score was calculated using ICD‐10 codes registered in the Danish National Patient Registry (DNPR) minimum 6 months before the first lymphoma diagnosis for the (matched) patient. 27 Comparators had to be alive and cancer‐free at the start of follow‐up (index date) for the matched patient. HDT‐ASCT‐treated patients were compared to non‐lymphoma comparators to assess if the infection risk normalized to that of the general population. Since patients in long‐term remission are often managed outside specialized haematology clinics, including by general practitioners in case of curable lymphomas, this comparison was considered informative.
The primary outcome was severe infections defined as infections requiring hospitalization. In practice, hospitalizations with infections as the primary or secondary DNPR discharge diagnosis were counted as events (Table S2). Differences in the occurrence of infection types were exploratory outcomes.
Comorbidities were identified using Anatomical Therapeutic Chemical (ATC) and ICD‐10 codes (Table S3). ATC codes from the National Prescription Registry (NPR) were used to identify drug prescriptions. 28 Congestive heart failure was defined as a combination of registered diagnoses in the DNPR and the prescription of loop diuretics (ATC C03C). 29 , 30 Hypertension was defined as receiving ≥2 different categories of antihypertensive drugs. 30 Diabetes was defined as receiving glucose‐lowering drugs (ATC group A10) in ≥2 quarters. Other comorbidities were based on ICD‐10 codes in the DNPR.
Prescriptions of anti‐infective agents for infections treated in the outpatient setting were a secondary outcome. In Denmark, all antibiotics and antivirals require prescriptions from an authorized physician. This analysis focused on infections occurring ≥5 years after HDT‐ASCT as patients are likely to receive oral anti‐infectives directly from the haematology departments, especially early in the follow‐up period, which is not captured in the NPR. Patient follow‐up at the haematology departments was typically terminated 5 years post‐HDT‐ASCT at the earliest for curative diseases. Anti‐infective agents were categorized as antiviral, antimycotic/antiparasitic agents and antibiotics. The latter were subdivided into narrow and broad‐spectrum agents (Table S4). Prescriptions within 14 days were counted as a single event.
STATISTICS
Follow‐up was the time from the index date until the first occurrence of competing events or censoring (emigration or 31 December 2018). Death, relapse and anti‐cancer treatment after HDT‐ASCT were considered competing events. Follow‐up was terminated 60 days before the first treatment day of a new anti‐cancer treatment. Rituximab monotherapy and radiotherapy sessions started <3 months after HDT‐ASCT were not considered competing events, as these treatments are often used as planned consolidation or maintenance therapy after HDT‐ASCT (Table S5). Overall survival (OS) was estimated using the Kaplan–Meier estimator, and median follow‐up was calculated using the reverse Kaplan–Meier method.
The incidence rate ratio (IRR) of infections between patients and comparators was calculated using Poisson regression with the logarithm of person‐time as offset. 31 The cumulative risk of infections was computed using the Aalen–Johansen estimator to account for competing events. The 2‐year cumulative risks of second and third infections were conditioned on the occurrence of a first and second infection respectively.
To study the effects of HDT‐ASCT on infections over time, landmark analyses were conducted with start dates 2 and 5 years after HDT‐ASCT. For the matched cohorts with the index date set at the 2‐ and 5‐year mark, the IRR was calculated with follow‐up restricted to 5 and 10 years after HDT‐ASCT respectively.
Risk differences for infections between patients and comparators were determined using pseudo‐observations and generalized estimation equations. 32 Univariate Cox analyses were conducted among patients to assess the impact of age, sex, time from lymphoma diagnosis until HDT‐ASCT, lymphoma subtypes and comorbidities on the risk of infections.
The study was registered at the North Denmark Region research registry (ID: 2021‐078).
RESULTS
Among 1073 HDT‐ASCT‐treated patients identified between 2000 and 2017, 781 fulfilled the inclusion criteria and were matched to 3905 comparators from the Danish background population (Figure S1). The median age was 57 years (range: 19–73), the female:male ratio was 1:1.9 and the median CCI score was 0 (Table 1). Median follow‐up was 7.7 years for patients and 7.6 for comparators. Five‐year OS from index date was 74.8% (95% confidence interval (CI): 71.8%–77.9%) for patients and 95.7% (95% CI: 95.0%–96.3%) for comparators (Figure S2). The median time from first lymphoma diagnosis to HDT‐ASCT (stem cell infusion date) was 7.5 months (interquartile range (IQR): 5.3–21.1), which differed between lymphoma subgroups according to earlier treatment lines (Table 1).
TABLE 1.
Baseline characteristics at the time of inclusion for patients and matched comparators.
| Comparators | All patients | DLBCL | FL | HL | MCL | PTCL | |
|---|---|---|---|---|---|---|---|
| Patients, N | 3905 | 781 | 265 | 57 | 93 | 219 | 147 |
| Male, N (%) | 2545 (65) | 509 (65) | 157 (59) | 31 (54) | 50 (54) | 170 (78) | 101 (69) |
| Median age (range) | 57 (19–73) | 57 (19–73) | 58 (21–71) | 56 (28–69) | 36 (19–68) | 60 (29–73) | 56 (20–72) |
| Median follow‐up time, years (CI 95%) | 7.6 (7.4–7.7) | 7.7 (6.9–8.5) | 8.4 (7.4–10.2) | 6.9 (4.4–10.5) | 9.3 (7.4–11.4) | 7.0 (6.1–8.3) | 6.8 (5.9–9.0) |
| HDT‐ASCT in first‐line consolidation, N (%) | 411 (52.6) | 79 (29.8) | <5 | <5 | 206 (94.1) | 120 (81.6) | |
| CCI score 0, N (%) | 3090 (79) | 618 (79) | 212 (80) | 50 (88) | 77 (83) | 169 (77) | 110 (75) |
| CCI score ≥1, N (%) | 815 (21) | 163 (21) | 53 (20) | 7 (12) | 16 (17) | 50 (23) | 37 (25) |
Note: Patients with aggressive transformation of indolent lymphoma were considered treated in the first line if HDT‐ASCT was the first treatment for transformed lymphoma regardless of earlier treatments for initial lymphoma diagnosis. Of patients with DLBCL, 72 (27%) had transformed disease prior to receiving HDT‐ASCT.
Abbreviations: CCI, Charlson Comorbidity Index; DLBCL, diffuse large B‐cell lymphoma; FL, follicular lymphoma; HDT‐ASCT, high‐dose therapy and autologous stem cell transplantation; HL, Hodgkin lymphoma; MCL, mantle cell lymphoma; PTCL, peripheral T‐cell lymphoma.
Risk of severe infections
The IRR of infections between patients and comparators from 90 days until 2 years post‐HDT‐ASCT was 8.43 (95% CI: 6.98–10.16). The IRR decreased to 2.82 (95% CI: 2.18–3.65) from 2 to 5 years post‐HDT‐ASCT and to 1.44 (95% CI: 1.03–2.01) after 5–10 years.
The cumulative risks of the first infection in patients and comparators are shown in Figure 1. The 2‐year cumulative risks of the first infection from the index date were 23.7% (95% CI: 20.7%–26.7%) for patients and 3.4% (95% CI: 2.9%–4.0%) for comparators.
FIGURE 1.
The cumulative risk of the first infection (with 95% CI) (A) from index date 90 days post HDT‐ASCT, (B) 2 years post HDT‐ASCT and (C) 5 years post HDT‐ASCT. Rematching was done at each landmark.
At 2 and 5 years post‐HDT‐ASCT landmarks, the 2‐year cumulative risks of infections were 10.1% (95% CI: 7.4%–12.8%) and 7.8% (95% CI: 4.4%–11.2%) for patients versus 3.9% (95% CI: 3.1%–4.7%) and 4.7% (95% CI: 3.5%–5.9%) for comparators respectively (Table 2).
TABLE 2.
Two‐year cumulative risks (%) of infections requiring hospitalization.
| Number at risk, patients/comparators | Patients, 2‐year cumulative risk | Comparators, 2‐year cumulative risk | |
|---|---|---|---|
| From index | |||
| 1st infection | 781/3905 | 23.7 (20.7–26.7) | 3.4 (2.9–4.0) |
| 2nd infection | 233/449 | 22.0 (16.7–27.3) | 8.3 (5.7–10.8) |
| 3rd infection | 77/167 | 23.4 (13.9–32.8) | 11.4 (6.6–16.2) |
| From 2 years | |||
| 1st infection | 495/2475 | 10.1 (7.4–12.8) | 3.92 (3.1–4.7) |
| 2nd infection | 85/282 | 16.6 (8.7–24.6) | 6.0 (3.3–8.8) |
| 3rd infection | 23/105 | 30.4 (11.6–49.2) | 5.7 (1.3–10.2) |
| From 5 years | |||
| 1st infection | 269/1345 | 7.8 (4.4–11.2) | 4.7 (3.5–5.9) |
Note: The 2‐year cumulative risk of the second infection was conditioned on the patient/comparator already having the first, and the risk of the third infection was conditioned on having the second infection. Rematching was done at each landmark.
For persons with ≥1 infection, the 2‐year cumulative risk of a second infection was 22.0% (95% CI: 16.7%–27.3%) for patients and 8.3% (95% CI: 5.7%–10.8%) for comparators (Table 2).
The risk of infections was consistently increased across sex, age, lymphoma subtype and period during which the patient received HDT‐ASCT (Figure 2). The risk difference (RD) between patients and comparators was lower for males, patients with the FL subtype and those treated in the 2011–2018 period compared to 2000–2010 (Figure 2).
FIGURE 2.
Two‐year cumulative risk difference of infections between patients and comparators by clinicopathologic features and time era.
Type of infections
Respiratory tract infection was the most frequent type, and the 2‐year cumulative RD of respiratory tract infection between patients and comparators was 10.9% (95% CI: 8.6%–13.3%) (Tables S6 and S7). At landmark analyses 2 and 5 years post‐HDT‐ASCT, the 2‐year cumulative RDs for infections of the respiratory tract were 5.3% (95% CI: 2.9%–7.6%) and 3.4% (95% CI: 0.6%–6.2%) respectively (Figure 3; Table S7).
FIGURE 3.
Two‐year risk difference with 95% CI for specific infections between high‐dose therapy and autologous stem cell transplantation (HDT‐ASCT)‐treated patients and comparators from index date and from 2 and 5 years post HDT‐ASCT landmarks. Rematching was done at each landmark. *Intraabdominal, hepatic, splenic or gastrointestinal infections. **Either unknown pathogen or pathogens other than viral or bacterial.
For 49.1% of severe infections, the discharge diagnosis contained information on the infectious pathogen type (bacterial/viral/parasitic/fungal, e.g. J020 Streptococcal pharyngitis). The 2‐year cumulative RD of bacterial infections was 7.7% (95% CI: 5.6%–9.7%) and 6.2% (95% CI: 4.5%–7.9%) for viral infections. The 2‐year cumulative RD for infections over time by pathogen type and location is shown in Figure 3.
Risk factors for severe infections among HDT‐ASCT‐treated patients
In the univariate analyses, age per year increase was borderline associated with the risk of infections among patients (hazard ratio (HR) 1.01, 95% CI: 1.00–1.02 per year) (Table 3). Investigated comorbidities were not significantly associated with the risk of infections; HR was 1.40 (95% CI: 0.85–2.33) for chronic lower respiratory diseases, 1.29 (95% CI: 0.75–2.21) for diabetes mellitus, 1.28 (95% CI: 0.77–2.12) for cardiovascular disease, 1.20 (95% CI: 0.89–1.64) for hypertension and 0.94 (95% CI: 0.48–1.83) for connective tissue disorders. Gender, lymphoma subtype and time from first lymphoma diagnosis until HDT‐ASCT had no significant impact on the risk of infections (Table 3).
TABLE 3.
Risk factors for the first infection requiring hospitalization among HDT‐ASCT‐treated patients.
| Risk factor | HR (95% CI) | p‐value |
|---|---|---|
| Age (per year) | 1.01 (1.00–1.02) | 0.053 |
| Female (n = 272) (ref.) | 1 | 0.180 |
| Male (n = 509) | 0.83 (0.64–1.09) | |
| Time from first lymphoma diagnosis until HDT‐ASCT (per month) | 1.00 (0.99–1.01) | 0.885 |
| DLBCL (n = 265) (ref.) | 1 | 0.776 |
| FL (n = 57) | 0.70 (0.38–1.29) | |
| HL (n = 93) | 1.04 (0.69–1.57) | |
| MCL (n = 219) | 1.05 (0.76–1.46) | |
| PTCL (n = 147) | 1.03 (0.71–1.49) | |
| Connective tissue disorders (n = 34) | 0.94 (0.48–1.83) | 0.860 |
| Chronic lower respiratory diseases (n = 41) | 1.40 (0.85–2.33) | 0.189 |
| Hypertension (n = 158) | 1.20 (0.89–1.64) | 0.237 |
| Cardiovascular disease (n = 51) | 1.28 (0.77–2.12) | 0.346 |
| Diabetes mellitus (n = 36) | 1.29 (0.75–2.21) | 0.363 |
Note: The hazard ratios (HR) were calculated using univariate Cox analysis.
Abbreviations: HR, hazard ratio; HDT‐ASCT, high‐dose therapy and autologous stem cell transplantation; DLBCL, diffuse large B‐cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma; MCL, mantle cell lymphoma; PTCL, peripheral T‐cell lymphoma.
Prescriptions for anti‐infective drugs
In years 5–10 after HDT‐ASCT, the annual rate of anti‐infective prescriptions was 3.93 (95% CI: 3.80–4.06) for patients and 2.47 (95% CI: 2.42–2.51) for comparators. The IRR for anti‐infectives was 1.59 (95% CI: 1.53–1.65). From the 5‐year post‐HDT‐ASCT landmark, the 2‐year cumulative RD for receiving at least one anti‐infective drug prescription was 15.9% (95% CI: 9.4%–22.5%) between patients and comparators (Figure 4). The use of both narrow‐ and broad‐spectrum antibiotics was more frequent in patients with a 2‐year RD at 10.9% (95% CI: 4.1%–17.7%) and 18.1% (95% CI: 11.5%–24.8%) respectively.
FIGURE 4.
Two‐year risk difference between high‐dose therapy and autologous stem cell transplantation (HDT‐ASCT)‐treated patients and comparators for receiving at least one anti‐infective drug prescription starting from the 5 years post HDT‐ASCT landmark.
DISCUSSION
This nationwide study investigated the risk of severe late infections after HDT‐ASCT relative to comparators. Relapse and new anti‐cancer treatment after HDT‐ASCT were treated as competing events as the aim was to report risk in the subset of patients with durable remissions after HDT‐ASCT. Patients had a higher risk of infections up to 10 years after treatment.
Two Swedish studies have investigated the infection rate ratio between patients treated with HDT‐ASCT for MCL and a matched background population. The first study investigated severe infections 1 year after HDT‐ASCT until the end of follow‐up and found an IRR of 5.62 (95% CI: 4.20–7.52). 14 In the present study, the IRR of severe infections was 8.43 from 90 days until 2 years post‐HDT‐ASCT. The difference could be explained by differences in study designs related to capping of follow‐up at 2 years in the present study, which also showed decreasing IRR over time. The Swedish study also included non‐HDT‐ASCT‐treated patients with MCL. The IRR for infections relative to the background population was similar for patients who did not receive HDT‐ASCT (IRR 4.66, 95% CI: 3.62–5.99), suggesting that the risk of infections may be explained by the underlying disease and treatments in general. However, the non‐HDT‐ASCT‐treated patients had a higher median age and burden of comorbidity than patients who received HDT‐ASCT. In contrast to the present study, the Swedish study continued follow‐up despite lymphoma relapse or new treatment, thereby assessing infection risk throughout the disease course regardless of intercurrent events. The second Swedish study of patients with MCL found an overall IRR of 2.14 (95% CI: 2.01–2.27) for combined cases of hospitalization with infection or anti‐infective drug prescriptions; however, only 19% received HDT‐ASCT. 33 When censoring at second‐line treatment initiation, the IRR of infections was increased for 7 years. 33
The present study also investigated risk factors for infections among HDT‐ASCT‐treated patients. Age was the only factor associated with increased infection risk. Since all patients were eligible for HDT‐ASCT, the included comorbidities were likely mild and possibly without influence on the risk of infections. Furthermore, few patients had comorbidities, elevating the risk of type II errors. This could explain the contrast to findings in general population studies, where the examined comorbidities were associated with higher infection risk. 34 , 35 , 36 , 37 , 38 Some patients, especially those who received multiple treatment lines, may have developed treatment‐related comorbidities not considered in our study as only comorbidities registered 6 months before the lymphoma diagnosis were included. Lymphoma subtype did not significantly influence infection risk, despite differences in the number of treatment cycles prior to HDT‐ASCT, whether administered as first‐line therapy or at relapse. These findings are consistent with an earlier study that found no difference in infection risk after HDT‐ASCT between patients with lymphoma, multiple myeloma and solid tumours. 5
CAR‐T is an approved alternative to HDT‐ASCT for some patients with R/R DLBCL, FL or MCL. For both second‐ and third‐line CAR‐T, limited data on infections ≥100 days post‐treatment has been published. 39 , 40 , 41 , 42 , 43 In the ZUMA‐7, TRANSFORM and BELINDA trials, CAR‐T was investigated as a second‐line treatment for R/R DLBCL. In the ZUMA‐7 trial, severe infections occurred in 28 (16.5%) CAR‐T‐treated patients and 20 (11.9%) HDT‐ASCT‐treated patients, but the time from treatment until infection was not reported. 44 Persistent neutropenia following treatment is likely the most impactful contributor to late infections. 45 In the ZUMA‐7 trial, cytopenia 30 days after treatment differed between recipients of CAR‐T (29%) and HDT‐ASCT (19%). Prolonged (>6 months) neutropenia was found in six patients in the CAR‐T group (3.5%) and none in the HDT‐ASCT group. 40 , 44 A single‐centre study of 139 patients also showed higher rates of severe infection in long‐term CAR‐T responders than HDT‐ASCT responders after 1 year (HR 3.06, 95% CI: 1.14–8.21). 46 The difference remained after excluding patients with a prior HDT‐ASCT treatment.
Infection density has been investigated in studies of patients receiving CAR‐T in later treatment lines. A study of 142 CAR‐T recipients with R/R DLBCL found 0.20 severe infections per 100 days at risk on days 29–180, decreasing to 0.16 on days 181–365 after treatment. 20 In a 2‐year follow‐up study of 249 CAR‐T recipients, 12 (5%) experienced severe infections >90 days after treatment. 47 Another study of 86 one‐year CAR‐T survivors reported 0.55 infections per 100 days at risk, of which 20% required hospitalization >90 days after CAR‐T. 23 However, late severe infections are a relatively rare outcome, and studies of long‐term toxicities after CAR‐T often include relatively small study populations. Moreover, third‐line CAR‐T studies might not be directly comparable to first/second‐line HDT‐ASCT due to possible increased infection risk from prior treatments. 45 Population studies on late infectious complications following CAR‐T in earlier treatment lines are needed to better evaluate the risks and benefits of CAR‐T versus HDT‐ASCT.
Respiratory tract infections were most frequent in HDT‐ASCT‐treated individuals, and the risk of respiratory infections was continuously increased for at least 7 years following treatment (Figure 3). HDT‐ASCT is associated with non‐infectious respiratory complications, potentially elevating the risk of respiratory tract infections. 48 , 49 A Danish national cohort study found a high incidence of pulmonary diseases among HL survivors compared to matched comparators. 48 These patients face an increased risk of lung toxicity due to frequent exposure to bleomycin. In a Norwegian study of HDT‐ASCT recipients from 1987 to 2008 for lymphomas, approximately 30% had moderate to severe pulmonary late effects, and an average reduction of 11% was observed in forced expiratory volume in 1 s compared to the general population. 49 A recent study also found that rituximab addition to CHOP therapy increased the risk of respiratory infections in patients with DLBCL in remission. 50 Pulmonary late effects and immunosuppression after lymphoma therapy could lead to an increased risk of lung infections. Vaccination programmes that cover influenza, pneumococcal and COVID‐19 are considered safe and effective. Although the effects are not documented in randomized trials in the lymphoma remission‐HDT‐ASCT setting, vaccine programmes are likely highly relevant measures against infections after HDT‐ASCT. 51 , 52
Our results based on anti‐infective drug prescriptions 5–10 years post‐HDT‐ASCT also showed an increased risk among treated patients (IRR 1.59). Patients were also more likely than comparators to receive broad‐spectrum antibiotics with a 2‐year RD of 18.1% 5 years post‐treatment. The Swedish population study reported an IRR of 13.35 (95% CI: 11.18–15.93) for systemic antimycotics, 1.92 (95% CI: 1.77–2.08) for systemic antibacterials and 7.94 (95% CI: 4.72–13.34) for systemic antivirals in patients with MCL compared to matched persons. 33 Contrary to the present study, this analysis was conducted from the date of initial MCL diagnosis until the end of follow‐up (median follow‐up times were 2.9 years for patients and 5 for comparators) without censoring for relapse or new lymphoma therapy. The increased prescription rate could be biased by healthcare professionals being more prone to prescribe anti‐infectives to lymphoma survivors with real or perceived compromised immunity. In addition, some patients with chronic lymphomas are followed lifelong in specialized settings with easier access to care than the general population.
The strengths of this study were the use of nationwide registers with prospectively collected data with high completeness and coverage. No patients were lost to follow up. Limitations include possible underestimation of the infection risk for HDT‐ASCT‐treated patients as they represent a generally healthy group when they were deemed eligible for HDT‐ASCT. Therefore, they may have been healthier than the matched background population even though they have the same CCI score and per se have a lower non‐lymphoma‐associated risk of infections. On the other hand, the much lower threshold for admitting patients treated with HDT‐ASCT due to infections would bias results in the opposite direction. Finally, infection‐prophylaxis data were not available, but prophylactic antifungal and antibiotic treatment would be uncommon 90 days after HDT‐ASCT, where patients were included.
In conclusion, this study found that HDT‐ASCT‐treated patients in remission had an increased risk of severe infections for up to 10 years post‐HDT‐ASCT compared to the general population. Respiratory tract infections were the most frequent type of infection leading to hospitalization.
AUTHOR CONTRIBUTIONS
Conception and design: TCEG, FTS, LHJ and MRS. Data collection: PJ, PdNB, JMJ, TSL and CBP. Statistical analyses: MRS, LHJ and RKJ. Interpretation of results, revision of manuscript and approval: All authors. Drafting of the first version of manuscript: FTS, TCEG, EFM, MRS.
FUNDING INFORMATION
This work was supported by a grant from the Lundbeck Foundation to the Innovation Centre Denmark, Silicon Valley, to fund Danish American Research Exchange for FTS at the Division of Hematology at Stanford University Medical Center, California. TCEG received financial support from the Danish Cancer Society (grant ID R274‐A17146). FTS received a grant from the Danish Lymphoma Group. MRS was supported by the Danish Data Science Academy, which is funded by the Novo Nordisk Foundation (NNF21SA0069429) and VILLUM FONDEN (40516).
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Supporting information
Data S1.
ACKNOWLEDGEMENTS
We would like to acknowledge all who contributed to the Danish Lymphoma Registry and the Danish Clinical Quality Program (RKKP).
Severinsen FT, Simonsen MR, Futtrup Maksten E, Jakobsen LH, Jensen RK, Søgaard KK, et al. Late infections after high‐dose therapy and autologous stem cell transplantation for lymphoma: A Danish population‐based study. Br J Haematol. 2025;207(3):920–928. 10.1111/bjh.20262
Freja Tang Severinsen and Mikkel Runason Simonsen shared first authorship.
Contributor Information
Freja Tang Severinsen, Email: freja.severinsen@rn.dk.
Mikkel Runason Simonsen, Email: mikkel.simonsen@rn.dk.
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Supplementary Materials
Data S1.