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Factors associated with prolonged length of in-hospital stay and higher mortality in patients with COVID-19 and lymphoma

Aug 9, 2021
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Patients with lymphoma have an increased risk of infections, both in incidence and severity, due to disease- and treatment-related immune dysregulation, and these patients are at increased risk of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and death due to coronavirus disease 2019 (COVID-19). There is, however, limited evidence on the incidence of, risk factors, and outcomes associated with persistence and mortality of COVID-19 in patients with lymphoma. The Lymphoma Hub has previously reported on management guidelines for lymphoma and COVID-19.

In a recently published study in American Journal of Hematology, Duléry et al.1 examined prolonged length of in-hospital stay (LOS) due to COVID-19 among patients with lymphoma and assessed its determinants and outcomes. 

Study design

This was a retrospective multicenter study of adult patients with past or current lymphoma admitted for COVID-19 to one of 16 French hospitals in March and April 2020. COVID-19 was confirmed via polymerase chain reaction from oropharyngeal or nasopharyngeal swabs or via clinical history and the typical COVID-19 ground glass opacities seen on computed tomography. Patients with lymphoblastic and lymphocytic lymphomas were excluded from the study. Data variables included symptoms, laboratory tests, imaging results, specific medications, oxygenation supply, and modality of hospital discharge. Prolonged LOS was defined as persisting or recurring COVID-19 symptoms requiring a total LOS of >30 days.

Results

Baseline characteristics

There were 111 patients included in the study; the median age was 65 years (range, 19–92 years) and 63% of patients were male. The median LOS was 14 days (range, 1–235 days) and at a median follow-up of 191 days (range, 3–260 days), the 6-month overall survival was 69% (95% confidence interval, 60–78). The baseline characteristics of patients with lymphoma and COVID-19 according to clinical evolution are presented in Table 1.

Table 1. Baseline characteristics according to clinical evolution of patients*

Characteristics, % (unless otherwise stated)

Total
(N = 111)

Died within 30 days
(n = 24)

Prolonged LOS for COVID-19 >30 days
(n = 32)

Survived >30 days with LOS for COVID-19 ≤30 days
(n = 55)

Comorbidities

 

 

 

 

              Comorbidity ≥1

68

88

69

58

              Hypertension

41

63

31

36

              Diabetes

20

33

16

16

              Chronic lung disease

9

13

9

7

              Cancer

13

25

6

11

              HIV infection

2

0

3

2

Histological subtypes

 

 

 

 

              Hodgkin lymphoma

8

4

3§

13

              DLBCL

38

63

31

31

              FL

20

0

38

18

              MZL

13

8

9

17

              MCL

9

13

13

5

              Other BCL

5

4

6

5

              T-cell lymphoma

7

8

0

11

Lymphoma treatment

 

 

 

 

              Any

71

75

81

64

              Anti-CD20 monoclonal               antibody

57

62

81

40

                            Induction

45

54

56

35

                            Maintenance

12

8

25

5

              Bendamustine

9

21

9

4

Lymphoma status at COVID-19 diagnosis

 

 

 

 

              CR

47

33

59

46

              PR

3

0

6

2

              Ongoing therapy <3 lines

27

42

16

27

              Watch and wait

11

4

3

18

              R/R

12

21

16

7

Median time between diagnosis of lymphoma and hospitalization for COVID-19 (range), months

24 (0–285)

15 (1–246)

35 (3–285)

13 (0–201)

BCL, B-cell lymphoma; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HIV, human immunodeficiency virus; LOS, length of in-hospital stay; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; PR, partial remission; R/R, relapsed/refractory.
*Adapted from Dulery, et al.1
Defined as chronic obstructive pulmonary disease, asthma, or chronic bronchitis.
Treatment administered within the previous 12 months before hospitalization for COVID-19.
§
Nodular lymphocyte-predominant Hodgkin lymphoma.

Characteristics and clinical evolution of patients with prolonged LOS for COVID-19

  • In total, 29% of patients had a prolonged LOS for COVID-19 symptoms, and the median LOS was 58 days (range, 31–235 days).
  • The median age of patients with a prolonged LOS was 64 years (range, 43–87 years) and 63% were male.
  • Three patients with prolonged LOS had an ongoing autoimmune disease, and one patient was being treated for HIV infection; overall, 69% of patients had at least one significant comorbidity.
  • In addition, 81% of patients with lymphoma were treated within the 12 months prior to hospitalization for COVID-19, and all these patients had been treated with an anti-CD20 monoclonal antibody, either as induction therapy (with chemotherapy) or as maintenance therapy (Table 1).
    • On the contrary, only 40% of patients who were alive 30 days after COVID-19 diagnosis without prolonged LOS had recently received an anti-CD20 monoclonal antibody (p < 0.001).
  • Three patients had a prolonged LOS as a result of both persistent COVID-19 symptoms and lymphoma progression.
  • Overall, 58% of patients with prolonged LOS for COVID-19 were admitted to the intensive care unit and 27% died (18% due to COVID-19 and 6% due to multiple causes, including lymphoma progression).

Laboratory findings and virological monitoring

The most common laboratory findings at admission included elevated C-reactive protein (>5 mg/L) in 91%, hypogammaglobulinemia (<4 g/L) in 32%, and lymphopenia (<1 g/L) in 70% of patients. Five of 32 patients had negative polymerase chain reaction tests at time of diagnosis, though diagnosis of SARS-CoV-2 pneumonia was established in all five and COVID-19 was later confirmed in four of the five patients.

Risk factors

Factors associated with longer LOS in univariate analysis included age ≥70 years, the presence of comorbidity, hypertension, non-Hodgkin lymphoma subtype, relapsed/refractory lymphoma, recent use of bendamustine, and recent anti-CD20 treatment (Table 2).

In multivariate analysis, increased LOS was also significantly associated with age ≥70 years (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.32–4.17; p = 0.004), relapsed/refractory lymphoma (sub-distribution HR [sHR], 3.12; 95% CI, 1.13–8.61; p = 0.028), and recent administration of anti-CD20 monoclonal antibody (sHR, 2.26; 95% CI, 1.42–3.60; p < 0.001). In addition, age ≥70 years (HR, 4.08; 95% CI, 1.94–8.57; p < 0.001), relapsed/refractory lymphoma (HR, 3.34; 95% CI, 1.58–7.06; p = 0.002), and recent administration of anti-CD20 monoclonal antibody (HR, 2.17; 95% CI, 1.04–4.52; p = 0.039) were associated with an increased risk of death in the multivariate analysis. The presence of comorbidities demonstrated an increased trend towards longer LOS (sHR, 1.50; 95% CI, 0.91–2.48; p = 0.109) and risk of death (HR, 2.50; 95% CI, 0.95–6.57; p = 0.064).

Table 2. Univariate analyses of the determinants of LOS and OS*

Factor

LOS

OS

sHR (95% CI)

p value

sHR (95% CI)

p value

Gender (male vs female)

1.11 (0.70–1.76)

0.665

1.47 (0.70–3.07)

0.307

Age ≥70 years

2.49 (1.47–4.21)

0.001

4.73 (2.30–9.75)

<0.001

Comorbidities (≥1 vs 0)

1.98 (1.24–3.14)

0.004

3.42 (1.32–8.85)

0.011

Hypertension

1.64 (1.01–2.66)

0.044

2.34 (1.19–4.62)

0.014

Histological subtype (vs B-cell NHL)

 

 

 

 

              T-cell               lymphoma

0.65 (0.28–1.51)

0.318

0.71 (0.17–2.96)

0.636

              Hodgkin               lymphoma

0.43 (0.20–0.90)

0.024

0.28 (0.04–2.07)

0.214

Time from lymphoma diagnosis to admission for COVID-19 (>12 months)

1.00 (1.00–1.01)

0.480

1.00 (1.00–1.01)

0.455

Lymphopenia (<1 G/L)

1.55 (0.96–2.51)

0.071

2.67 (1.02–6.97)

0.044

Hypogammaglobulinemia (<4 g/L) §

1.45 (0.67–3.13)

0.339

1.30 90.42–4.03)

0.649

Lymphoma treatment

 

 

 

 

              Anti-CD20               monoclonal               antibodyǁ

1.83 (1.16–2.89)

0.009

1.60 (0.78–3.29)

0.198

              Bendamustineǁ

3.37 (1.06–10.73)

0.039

3.26 (1.42–7.52)

0.006

              Any lymphoma               therapyǁ

1.45 (0.89–2.37)

0.140

1.27 (0.58–2.81)

0.55

              R/R lymphoma

3.64 (1.32–9.98)

0.012

3.43 (1.63–7.18)

0.001

CI, confidence interval; LOS, length of in-hospital stay; NHL, non-Hodgkin lymphoma; OS, overall survival; R/R, relapsed/refractory; sHR, sub-distribution hazard ratio.
*Adapted from Dulery, et al.1
Indicates p values of <0.05 to denote statistical significance.
Missing data in six patients.
§
Missing data in 45 patients.
ǁ
Treatment administered within the previous 12 months before hospitalization for COVID-19.

Conclusion

This retrospective study identified several factors associated with increased LOS in patients with lymphoma and COVID-19, including age, comorbidities, relapsed/refractory lymphoma status, recent administration of bendamustine, and anti-CD20 monoclonal antibody treatment. In addition, factors such as age, comorbidities, relapsed/refractory lymphoma, and anti-CD20 monoclonal antibody treatment were associated with decreased overall survival in patients with lymphoma. Identification of these factors supports the impact that B-cell depletion has on the course of COVID-19 and may help to inform the medical management of patients with lymphoma, including the evaluation of specific therapeutic approaches and the efficacy and timing of COVID-19 vaccination in patients with lymphoma.

  1. Duléry R, Lamure S, Delord M, et al. Prolonged in-hospital stay and higher mortality after COVID-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy. Am J Hematol. 2021;96(8):934-944. DOI: 1002/ajh.26209

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