Protective role of Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukaemia and COVID‐19

Severe cases of coronavirus disease 2019 (COVID‐19) are usually accompanied by an exuberant immune response comparable to cytokine release syndrome (CRS), with markedly elevated serum levels of pro‐inflammatory cytokines that are thought to be a major drivers of morbidity and mortality for these patients. ¹ Several drugs with anti‐inflammatory properties (tocilizumab, siltuximab, sarilumab, anakinra, among others) have been suggested as adjuncts to supportive care in the management of COVID‐19, and several clinical trials are underway (ClinicalTrials.gov Identifier: NCT04315298, NCT04317092, NCT04306705).

The Bruton tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib and zanubrutinib are commonly used to treat chronic lymphocytic leukaemia (CLL), Waldenström macroglobulinaemia (WM), and chronic graft‐versus‐host disease (GvHD) and have been shown to have potent anti‐inflammatory effects resulting in decreased levels of pro‐inflammatory cytokines that are commonly elevated in severe COVID‐19. ² Furthermore, these drugs may abate some noxious pulmonary effects of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and other similar viruses, reducing the degree of lung injury and disease‐related mortality. ^{3 , 4} Clinical trials examining the potential benefit of BTKi in COVID‐19 are underway (ClinicalTrials.gov Identifier: NCT04382586, NCT04346199).

A recent study ⁵ described the outcomes of six patients with COVID‐19 with WM receiving ibrutinib. Five of the six had mild symptoms, did not require hospitalisation, and recovered promptly. One of the six required hospitalisation and mechanical ventilation but eventually recovered fully. Acknowledging the limitations of this small study, the authors hypothesised that ibrutinib may protect against lung injury in patients infected with SARS‐CoV‐2, and therefore suggest BTKi continuation in patients with WM with COVID‐19.

It is unclear if the proposed protective effect of BTKi applies to patients with CLL, who have immune deregulation secondary to the underlying disease process. ⁶ Also, BTKi use in CLL is associated with increased risk of infection, especially viral. ⁷ Considering the high prevalence of CLL, studying outcomes of BTKi in patients with CLL with COVID‐19 and exploring whether to continue BTKi in this setting becomes highly relevant. We reviewed our institutional experience with this population, examining severity of disease and clinical outcomes. Our present study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai.

Eight patients with CLL receiving a BTKi were hospitalised for COVID‐19 within our healthcare system (seven ibrutinib, one acalabrutinib). The clinical characteristics of the patients are summarised in Table I. ⁵ The median (range) age was 72 (49–88) years. BTKi was held in six of the eight patients (‘BTKi‐held’) and continued in two (‘BTKi‐cont’). Two of the eight patients in the ‘BTKi‐held’ cohort developed severe respiratory failure and eventually died (Patient 6: ibrutinib for 3+ years, full dose of 420 mg daily, Patient 3: ibrutinib for <4 months, recommended reduced dose of 140 mg due to concomitant use of a strong cytochrome P450 3A4 [CYP3A4] inhibitor). All others had mild‐to‐moderate disease.

Table I.

Baseline characteristics of eight patients with B‐cell diagnoses on BTKi with COVID‐19 infection.

	BTKi‐held						BTKi‐continued
	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8
Demographics
Age, years	72	67	88	49	72	80	56	75
Gender	M	M	M	M	M	M	M	F
Race/ethnicity	NHB	Unknown	NHW	NHW	NHW	NHW	Unknown	Unknown
Comorbidities
Obesity[BMI > 30 kg/m2]	N	Y	N	N	Y	N	Y	N
Hypertension	Y	Y	Y	N	Y	Y	N	N
Diabetes	N	Y	N	N	Y	Y	Y	N
Hyperlipidaemia	N	N	Y	N	N	N	N	N
History of ASCVD	Y	N	N	N	Y	N	N	N
CLL disease characteristics
BTKi	Ibrutinib	Ibrutinib	Ibrutinib	Acalabrutinib	Ibrutinib	Ibrutinib	Ibrutinib	Ibrutinib
Dose of BTKi, mg/day	140++	420	140*	200	420	420	420	420
Time on BTKi, months	NA	18·9	3·8	16·1	NA	44·9	29·6	18·1
IVIG in last month	NA	N	N	N	NA	NA	Y	N
Normal IgG	NA	NA	Y	NA	NA	NA	Y	N
COVID‐19 presentation
CLL Diagnosis to COVID‐19 (months)	70·2	56·5	173·2	111·5	NA	68·5	78·7	106·9
Cough	Y	Y	Y	Y	N	N	Y	N
Fever	Y	Y	Y	Y	N	Y	Y	Y
Dyspnea	Y	Y	N	N	N	Y	N	N
Sore throat	N	Y	N	N	N	N	N	Y
Fatigue	N	Y	N	Y	N	N	Y	Y
Ageusia	N	N	N	N	N	N	Y	N
Anosmia	N	N	N	N	N	N	Y	N
Data at COVID‐19 diagnosis
WBC, K/µl	4·9	10·9	28·1	8·3	7·3	9·5	34·0	7·2
ALC, K/µl	1·2	0·9	10·3	4·4	1·7	2·1	21·7	0·8
Hb, g/l	134	152	88	151	134	152	135	140
Platelet count, K/µl	145	170	167	150	91	181	207	151
C‐reactive protein, mg/l	81·3	294	283·7	2·1	62·5	124·9	59·1	1·5
Ferritin, ng/ml	13,401	1,095	295	NA	NA	1,113	158	NA
D‐dimer, mlFEU	3·0	5·63	>20	NA	NA	3·08	0·4	0·28
IL‐1β, pg/ml	NA	0·7	0·5	NA	NA	NA	<0·3	<0·3
IL‐6, pg/ml	NA	87·3	53·0	NA	NA	NA	43·2	7·2
IL‐8, pg/ml	NA	24·8	18·0	NA	NA	NA	46·7	15·4
TNF‐α, pg/ml	NA	34·8	100·0	NA	NA	NA	22·0	16·7
Multifocal pneumonia	No	No	No	No	Yes	Yes	No	No
COVID‐19 outcomes
Hospitalisation	Y	Y	Y	Y	Y	Y	Y	Y
Length of stay, days	10	7	9	5	8	19	9	3
Max. oxygen requirement	NC	NC	HFNC	None	None	BIPAP	NC	None
COVID‐19 treatment	HC, AZ	HC	HC	HC, AZ, TOCI	HC, AZ	HC, AZ	HC	None
Death	N	N	Y	N	N	Y	N	N

M, male; F, female; NHB, non‐hispanic black; NHW, non‐hispanic white; ASCVD, atherosclerotic cardiovascular disease; CLL, chronic lymphocytic leukaemia; WM, Waldenström macroglobulinaemia; IVIG, intravenous immunoglobulin; IgG, immunoglobulin G; WBC, white blood cell count; ALC, absolute lymphocyte count; Hb, haemoglobin; IL, interleukin; TNF, tumor necrosis factor; NC, nasal cannula; HFNC, high‐flow nasal cannula; HC, hydroxychloroquine; AZ, azithromycin; TOCI, tocilizumab; ST, steroids, NA, not available. *Dose‐reduced due to concomitant use of strong a CYP3A4 inhibitor; ++Reason for dose reduction unclear.

Our observations support continuation of BTKi in patients with CLL throughout COVID‐19 infection, as they may provide some protection against noxious viral effects. Our findings concur with Treon et al. ⁵ in a cohort of patients with WM receiving ibrutinib. We acknowledge the limitations of our present study, namely its retrospective nature and small sample size. Further studies are needed to validate this proposed approach. The results of two clinical trials assessing the effect of zanubrutinib (NCT04382586) and acalabrutinib (NCT04346199) in hospitalised patients with COVID‐19 will help clarify the role of BTKi in this setting.

Notably, the two patients who continued on ibrutinib had short hospital stays, minimal oxygen requirements, and have since fully recovered. Neither of them developed significant adverse events (AEs) attributable to BTKi.

Discussion

The BTK pathway is critical to the production of multiple pro‐inflammatory cytokines. Inhibition of BTK signalling results in decreased cytokine levels, with a subsequent anti‐inflammatory effect ² . BTK signalling dysregulation in lung macrophages may be a key pathophysiological component of SARS‐CoV‐2‐related lung injury. ⁴ , ⁸ In mouse influenza models, use of BTKi successfully rescued mice from lethal acute lung injury. ³ Therefore, BTK pathway inhibition is a promising target to lessen the exaggerated immune response of severe COVID‐19 and its respiratory complications.

Recent studies show high severity of infection in patients with haematological malignancies who contract COVID‐19. ⁹ Despite the defects in immunity and subsequent infection risk in CLL, ⁶ six of our eight patients had mild‐to‐moderate disease severity, minimal oxygen requirements, and short hospital stays. The ‘BTKi‐cont’ cohort had particularly prompt recoveries. Apart from hydroxychloroquine, neither received other therapies that could have contributed to their favourable outcomes. Recognising the limitations of a small sample size, our present findings support those of Treon et al. ⁵ , suggesting that BTKi may indeed have protective effects against SARS‐CoV‐2 virulence.

The ‘BTKi‐held’ cohort may still have experienced some benefit from being on BTKi at the time of infection. The half‐life of ibrutinib and acalabrutinib with preserved renal function is only 4–7 h, but as BTKi bind covalently to BTK, pathway re‐activation requires de novo enzymatic synthesis, which occurs at highly variable rates across patients. ¹⁰ Some degree of BTK inhibition may therefore have persisted after drug clearance.

In a document released by the American Society of Hematology (ASH) to provide guidance on CLL management in patients with COVID‐19, experts conclude there is insufficient data to determine whether to continue BTKi in this setting. ¹¹ However, they advise caution with abrupt discontinuation of ibrutinib, which has been associated with a form of withdrawal syndrome resulting in significant cytokine release. ¹²

BTKi therapy in CLL increases risk of infections, especially pneumonia. ¹³ However, incidence of infection is highest in the first 6 months and then decreases over time. ¹⁴ Furthermore, long‐term BTKi therapy may allow for meaningful recovery of humoral immune function, ultimately leading to decreased infection rates. ¹⁵

No significant AEs attributable to BTKi were seen in the ‘BTKi‐cont’ cohort (i.e., haemorrhage, atrial arrhythmias). However, neither of them received full‐dose anti‐coagulation, use of which is becoming increasingly common to target the pro‐thrombotic effects of COVID‐19. BTKi should be used cautiously in this setting.