key: cord-0693334-06uklobn authors: Alsuliman, Tamim; Faict, Sylvia; Malard, Florent; Genthon, Alexis; Brissot, Eolia; van de Wyngaert, Zoe; Ikhlef, Souhila; Banet, Anne; Lapusan, Simona; Sestilli, Simona; Corre, Elise; 'Hammedi-Bouzina, Fella M; Schaeffer, Louis; Legrand, Ollivier; Dulery, Rémy; Mohty, Mohamad; Marjanovic, Zora title: Does Ibrutinib impact outcomes of viral infection by SARS-CoV-2 in mantle cell lymphoma patients? date: 2020-11-25 journal: Curr Res Transl Med DOI: 10.1016/j.retram.2020.103273 sha: 7066988ba05d098d52eec5daba99bdd1adb06cfc doc_id: 693334 cord_uid: 06uklobn nan Tamim Alsuliman 1 , Sylvia Faict 1 , Florent Malard 1,2 , Alexis Genthon 1,2 , Eolia Brissot 1,2 , Zoe van de Wyngaert 1,2 , Souhila Ikhlef, 1 We herein report on two cases of mantle cell lymphoma, presenting with COVID-19 symptoms, treated by ibrutinib 560 mg daily. Ibrutinib was discontinued for both patients and both fully recovered without need for ICU admission. Ibrutinib was reintroduced 4 weeks after full recovery. The protective effect of Bruton tyrosine kinase (BTK) anti-proinflammatory cytokines is well recognized in the treatment of certain cancers and immunity-related complications. Consequently, the rationale that BTKs may play a role in the treatment/control of severe COVID-19, may be valid. This effect however, may be limited in the viral infection setting due to J o u r n a l P r e -p r o o f predisposed high concentrations of interferon gamma, and to the probability of concomitant infections. Discontinuation policies should rely more widely on outcome experience, but case -by-case decisions should also be considered. Dear Editor, The subject of hematological malignancies treatment in the era of COVID-19 is of great importance as many teams are working hard to define the right balance: controlling the disease while not exposing their patients to the high risk of COVID-19. 1 Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor, widely used in the treatment of some lymphoproliferative diseases like mantle cell lymphoma and Waldenström's macroglobulinemia. 2 Treon et al. suggested a protective effect of ibrutinib on pulmonary injury in COVID-19 disease patients. They reported these protective effects on pulmonary injury of continuing or even increasing ibrutinib therapy at a maximal dose of 420 mg/day. All six patients were on ibrutinib treatment for Waldenström's macroglobulinemia. The only patient on a reduced dose of 140 mg of ibrutinib was also the only patient to develop respiratory insufficiency, which improved upon re-initiating ibrutinib, and subsequently quickly resolved upon increasing the dose to 420 mg/day. 3 They suggest that ibrutinib as a BTK inhibitor is able to inhibit and decrease the inflammatory cytokines that are activated through the toll-like receptor (TLR) pathway in epithelial ATII cells and alveolar macrophages. These cytokines are deemed responsible for the majority of pulmonary injury in COVID-19 disease. Herein we report on two patients treated at our center with ibrutinib, both with underlying mantle cell lymphoma. They had COVID-19 and developed respiratory illness. Both patients J o u r n a l P r e -p r o o f discontinued ibrutinib, and both fully recovered. We describe these two cases and discuss further, the possible mechanisms of action of ibrutinib in the context of COVID-19. Case 1: The first patient is a 71-year old male. He was contacted by his hematologist for a routine check-up. The patient had already significant dyspnea and unproductive cough. The patient refused to be admitted to hospital. One week later, the patient's status had worsen, and the emergency services were contacted. He was then admitted to hospital presenting with symptoms suggestive of COVID-19, including dyspnea with oxygen-dependence at 5 L/min, diarrhea and the hematologist immediately discontinued ibrutinib. This patient had a biological inflammatory syndrome with leukocytosis, neutrophilia at 10 000/µl, and C-reactive protein (CRP) at 204 mg/l. He also had a newly diagnosed lymphopenia of 570/µl. PCR result of SARS-CoV-2 were negative; however, a CT angiogram of the chest, performed on the second day of hospitalization, was very suggestive of COVID-19 pulmonary disease with bilateral ground glass opacities and nodular condensations, as shown in figure (1) and figure (2) . After performing blood cultures and following local guidelines, antibiotic treatment was started with ceftriaxone, which was subsequently switched to piperacillin/tazobactam 16 g/24h the same day. Azithromycin was added, the same day, at a dose of 500 mg on the first day followed by 250 mg for the next four days. Because of the high clinical suspicion of COVID-19 alongside the suggestive radiological features, and despite the initial negative PCR result, the patient started on an anti-IL-6R antibody that blocks the IL-6 pathway. The patient's status was ameliorated remarkably and progressively. He returned home on day 7 after admission. The patient tested serologically negative for COVID-19 antibodies more than 2 months after symptom initiation. Ibrutinib was reintroduced 6 weeks after the initial admission date, according to department guidelines, equal to 4 weeks of full recovery of COVID-19. The patient was treated for mantle cell lymphoma with ibrutinib at a dose of 560 mg, up from January 2019. Initial diagnosis was in April 2016, with first line treatment by R-CHOP followed by rituximab maintenance. At the end of maintenance treatment, disease relapse was noted in the cervical area, at which time ibrutinib treatment was started. Treatment was intensified and followed by autologous stem cell transplant. It is worth noting that the patient had some important comorbidities such as uncontrolled diabetes mellitus type 2, with HbA1c at 10.4%, and macro-angiopathic complications, including ischemic coronaropathy, carotid stenosis and peripheral obstructive disease. The second patient, also male, was treated for mantle cell lymphoma with ibrutinib at a dose of No adverse effects were registered on mantle cell lymphoma control for either of the two patients. Patients with COVID-19 experience mild to moderate disease in 80% of cases, the rest may present with severe symptoms leading to critical conditions for which there is mas sive concern due to the rapid viral dissemination and limited medical resources, even in developed countries. 4, 5 Patients with hematological malignancies and COVID-19 have an increased risk of death compared to the general population, depending on the age of the patient, time since diagnosis, disease status or type of hematological malignancy. (6) (7) (8) infections. 10, 11 Ren et al. found that ibrutinib could not block TNFα production in monocytes primed with IFNγ, or in co-cultures of monocytes and NK cells. Thus, they expect that it is likely that FcγRactivated monocytes can still produce not only IL-12, but also other chemokines/cytokines in mixed cellular environments. These cytokines could serve to activate neighboring cells. 12 When taken collectively, these data may suggest that although ibrutinib can effectively inhibit proinflammatory responses in isolated cells, its ability to do so within the whole organism may be limited, especially when the secretion of IFNy is increased. This may explain why early clinical results showed an enhanced effect when adding rituximab or ofatumumab to ibrutinib in the treatment for chronic lymphocytic leukemia. 13 Although ibrutinib is considered by some to be a potenti al promising treatment for pulmonary consequences of chronic graft-versus-host disease (cGVHD), 8 serious adverse events are usually the reason behind treatment discontinuation in almost 30% to 40 % of cases. These adverse events may include asthenia, pneumonitis, fungal and bacterial infections, while diarrhea of grade ≥3 occurs in more than two-thirds of patients. 14, 15 This may also explain the relatively good results for these two patients when discontinuing ibrutinib after being infected with SARS-CoV-2. No ICU hospitalization was needed, and no accompanying severe co-infections were reported. Although serological tests were negative for the first case and a PCR-confirmed COVID-19 couldn't be documented, highly suggestive radiological signs alongside the typical clinical manifestations (general, respiratory and digestive) in addition to high CRP level on admission 4 were indicative of COVID-19 infection. The delay between the first symptom and the PCR test was more than 11 days, the estimated median time needed for a positive-to-negative PCR test result conversion of upper respiratory tract samples. 10 With respect to the first case's laboratory tests, serological tests (IgM and IgG) could have rendered false-negative results in 10 to 30% of cases, according to a recent Cochrane systematic review. Moreover, no robust data to date are available to interpret test sensiti vity for results obtained beyond the 35th day of symptom initiation, as it was the case for our first patient. 16 The patient was treated by a recombinant human IL-6Rα antagonist. Could this treatment have affected antibody productivity in response to SARS-CoV-2 by blocking an important inflammatory pathway? In our opinion, this question is worth thorough discussion. 17 Finally, rapid clinical amelioration and an unaffected lymphoma control were observed in both cases suggesting a short temporary discontinuation policy success in our mantle cell lymphoma patients during the acute phase of COVID-19 infection. Although the protective effect of anti-proinflammatory cytokines may be rational when talking about BTKs, this effect may be limited to circumstances of viral infection due to predisposed high concentrations of interferon gamma and to the probability of concomitant infections. Continuation and discontinuation policies should rely more widely on outcome experience; meanwhile case-by-case decisions should also be considered. Informed consents were obtained from the patients for the publication of their cases FM reports lecture honoraria from Therakos/Mallinckrodt, Biocodex, Janssen, Keocyt, Sanofi, JAZZ pharmaceutical and Astellas, all outside the submitted work. RD reports lecture honoraria from Keocyt, Sanofi and Novartis, all outside the submitted work. TA reports honoraria from BIOTEST, outside the submitted work. Authors would like to thank the patients for their participation. Authors would like also to thank medical and paramedical staff of hematology and cell therapy department of Saint-Antoine hospital, AP-HP, Paris for their dedication to patients' service. J o u r n a l P r e -p r o o f Management of patients with multiple myeloma during the COVID-19 pandemic Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. P & T: a peer-reviewed journal for formulary management The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients A review of potential treatments to date in COVID-19 patients according to the stage of the disease How will country -based mitigation measures influence the course of the COVID-19 epidemic? 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