Tocilizumab for Severe SARS-COV-2 Infection in Patients with Lymphoma

  

    

    
Case 1 
    
Case 2 
    
Case 3 
  
  

    
Age (years)
    
68
    
80
    
55
  
  

    
Sex
    
M
    
M
    
M
  
  

    
Type of lymphoma
    
Follicular
    
Mantle cell
    
Mantle cell
  
  

    
Time from diagnosis (months)
    
47
    
36
    
45
  
  

    
1st line/time from last course (months)
    
BR/42
    
VRCAP/29
    
RCHOP-RDHAP/40
  
  

    
Time on rituximab maintenance (months)
    
24
    
26
    
33
  
  

    
Last rituximab dose (months)
    
13
    
2
    
3
  
  

    
Disease status
    
CR
    
CR
    
CR
  
  

    
COVID-19 severity
    
Moderate
    
Severe
    
Severe
  
  

    
Lymphocyte count (x109/L)
    
0.67
    
0.28
    
0.47
  
  

    
Neutrophil count (x109/L)
    
5.4
    
5.8
    
3
  
  

    
TP ratio
    
1.1
    
1.01
    
1.16
  
  

    
TTPA ratio 
    
1.3
    
1.13
    
1.17
  
  

    
D-dimer (n<0.5 mg/ml) 
    
0.6
    
0.6
    
2.6
  
  

    
PCR (n <5 ng/mL)
    
147
    
38.2
    
300
  
  

    
Procalcitonin (n <0.5 ng/mL)
    
0.26
    
0.27
    
0.88
  
  

    
LDH (n 135-250 U/L)
    
376
    
280
    
671
  
  

    
Comorbidities
    
HT
    
None
    
DM, HT, CRF
  
  

    
IgG (n 700-1600 mg/dL)
    
1278
    
603
    
394
  
  

    
IgA (n 70-400 mg/dL)
    
125
    
38
    
41
  
  

    
IgM (n 40-230 mg/dL)
    
89
    
17
    
9
  
  

    
Oxygen saturation (%)
    
98
    
89
    
88
  
  

    
Pneumococcal/Legionella antigen urine
    
Neg/Neg
    
Neg/Neg
    
Neg/Neg
  
  

    
Intensive care unit
    
No
    
No
    
No
  
  

    
Treatment
    

    

    

  
  

    
Hydroxychloroquine
    
Yes
    
Yes
    
Yes
  
  

    
Azytromycin
    
Yes
    
Yes
    
Yes
  
  

    
Corticosteroids
    
Yes
    
Yes
    
Yes
  
  

    
Ceftriaxone
    
Yes
    
Yes
    
Yes
  
  

    
Symptoms resolved/Death
    
Resolved
    
Death
    
Resolved
  
  

    
Days for resolution/Death
    
21
    
16
    
28
  
  

    
HT:    Hypertension; DM: Diabetes Mellitus; CRF: Chronic Renal Failure; CR: Complete    Remission
      
All data provided were    recorded on admission. 
  

Table 1: Characteristics of the patients reported.

Case Presentation

Case 1 was a patient diagnosed with follicular lymphoma and has remained in Complete Remission (CR) after 6 cycles of bendamustinerituximab and 2-year rituximab maintenance which he had ended up 13 months before admission. Four days after hospitalization he developed a high temperature and severe respiratory failure. No improvement was noticed with corticosteroid pulses. D-dimer, clotting screen and procalcitonin were normal at the time whereas ferritin (3200 ng/mL), CRP (159 mg/L), IL-6 (145 pg/mL) and LDH (268 U/L) levels were elevated. Two standard doses (8 mg/kg) of tocilizumab with a 12-hour interval were administered with rapid clinical and analytical (PCR 15 mg/L) improvement 48 hours later. He was discharged 11 days after admission.

Case 2 was in CR of mantle-cell lymphoma following 6 VRCAP courses and ongoing rituximab maintenance. Ten days after admission he developed progressive respiratory failure and new infiltrates in his chest X-ray unresponsive to corticosteroid pulses. Segmentary pulmonary embolism was also diagnosed and therapeutic-dose enoxaparin started with no change in respiratory status. Once IL-6 levels were found to be high (160 pg/pL) 2 standard tocilizumab doses were prescribed. At the time ferritin (4300 ng/mL), CRP (69 mg/L), LDH (459 U/L), D-dimer (2.5 pg/mL) and INR (1.5) were also found to be raised. Despite tocilizumab administration his respiratory failure continued to worsen and analytical parameters did not significantly change. He passed away 14 days after admission.

Case 3 was also a patient with mantle-cell lymphoma in CR following R-CHOP/R-DHAP (6 courses) and consolidation with autologous stem cell transplantation. He was on rituximab maintenance when he presented with SARS-COV-2 pneumonia. After 6 days in hospital he developed progressive respiratory failure, persistence of high fever and no improvement in his X-ray findings. IL-6 (243 pg/mL), ferritin (2350 ng/mL) and LDH (457 U/L) levels were found to be very elevated. He received 2 doses of tocilizumab with important clinical improvement within the next 2 days. Despite his comorbidities his clinical course was favorable and was discharged 17 days after admission.

Discussion/Conclusions

Since the arrival of COVID19 and the evidence of an involvement of a release of proinflammatory cytokines including Interleukins-6 IL-6) during the clinical illness, especially in severe cases, there has been an interest in the potential benefits of this drug for the treatment of severe SARS-COV-2 infection. Preliminary data from short series of patients have been encouraging but any evidence behind these data is lacking. In the hematological setting tocilizumab has only been licensed for the treatment of the cytokine release syndrome following CAR-T cell therapy [6]. IDSA guidelines support the use of tocilizumab in the setting on ongoing clinical trials whereas Italian guidelines of SARS-COV-2 infection management find off-label use of this drug acceptable in severe cases especially if IL-6 levels are >40 pg [7,8]. Measurement of serum IL-6 levels is important for decision making but not for further monitoring of treatment effectiveness. Contraindications to the use of tocilizumab comprise abnormal liver function tests (transaminase level >5 fold the upper limit of normal), low neutrophil or platelet count (<0.5 and 50x109/L respectively), documented sepsis (high procalcitonine levels may be indicative), complicated diverticulitis/intestinal perforation, cutaneous infection and immunosuppressive anti-rejection therapy). There are FDA black box warnings of serious infections with tocilizumab which makes involved physicians be particularly cautious with patient selection before use is raised.

Our report show that actually tocilizumab therapy might be of clinical interest in patients with lymphoma and severe SARS-COV-2 infection. Development of early intervention strategies aimed to avoid progressive respiratory failure eventually leading to longer hospital stays and ICU admission (even invasive ventilation) is key in severe COVID19 management. Results of ongoing trials must be awaited before any conclusions can be drawn but in the meantime off-label use of well selected patients may be of benefit and should be encouraged.

References

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