Table 1.
Agents Considered for the Treatment of COVID-19 Relevant to HCT, and Common Drugs Used in HCT Relevant to COVID-19 Infection
| Drug Name | COVID-19 Studies | Use in HCT | Special Considerations |
|---|---|---|---|
| Agents with the greatest promise | |||
| Remdesivir | Benefit in animal models against the MERS virus and SARS virus; therefore, may have potential activity against COVID-19 [31,32]. On May 2020, the FDA approved remdesivir for severely ill hospitalized patients [33]. A randomized study showed no statistically significant improvement in the primary endpoint [34]. | No definite role specifically in HCT. | Use only in the context of clinical trials. Can cause hepatotoxicity, thereby caution in patients with liver GVHD |
| Tocilizumab | Single-arm trial showing moderate/minimal impact on clinical outcomes [35]. Approved in China for treatment of COVID-19 complications [36]. | Used for the treatment of acute GVHD. | Reactivation of hepatitis B, hepatotoxicity, and serious infections can occur. |
| ARDS is usually associated with IL-6 increase thereby providing the rationale for anti-IL6 or anti-IL6 receptor antibody therapy [28,37]. | Also used for the treatment of cytokine release syndrome after CAR T cell therapy. | Consider avoiding in cases of active liver GVHD. | |
| Tocilizumab also increases the risk of secondary infections [38]. | If supply is an issue, then reserve it for COVID-19 patient clinical trials and use alternate agents for acute GVHD. | ||
| CAR T cell approved therapy may be affected due to the restricted availability of this drug; thus, consider limiting CAR T cell therapy to those with an urgent need. | |||
| Convalescent plasma recovered from COVID-19 patients | Failure of clinical improvement in 2 case series [39,40]. Hundreds of trials currently underway. Exact role in COVID-19 trials undefined. | Not used in GVHD or HCT. | Allergic reactions can occur. |
| Given the weak data on efficacy reported so far, it should be used only in clinical trials. | |||
|
Agents that likely will not work, according to the literature | |||
| Azithromycin | Tested in a French trial and found to reinforce the positive effect of hydroxychloroquine on the COVID-19 viral load [41]. | Used as a treatment for lung GVHD (BOS). | Can cause QTc prolongation, torsades de pointes, ventricular tachycardia, and sudden cardiac death, especially when used together with chloroquine. |
| A significant number of patients with GVHD will also be on “azoles” for antifungal prophylaxis, so the risk of QTc prolongation could be further enhanced if used concurrently with full-dose azithromycin, chloroquine, or both. | |||
| Chloroquine and hydroxychloroquine | Best evidence thus far has failed to demonstrate benefit in hard clinical outcomes, but some trial results have been encouraging, with a suggestion of reduced viral load or reduced PCR positivity of COVID-19 [42]. | Used occasionally to treat chronic GVHD. | Metabolized by cytochrome P450. Significant QTc prolongation. |
| One US retrospective analysis showed no benefit and association with higher mortality in patients receiving hydroxychloroquine [43]. Other studies have shown no benefit and potential harm, such as arrhythmias 44, 45, 46, 47. | Concerns about increased toxicity with cyclosporine and imatinib (used in chronic GVHD), such as myopathies. | ||
| Agents that possibly may work | |||
| Antivirals | |||
| Lopinavir/ritonavir | Recently published trials showed no significant effect on mortality. Very low-level evidence due to risk of bias, such as lack of blinding [48]. | No definite role specifically in HCT. | Severe GI symptoms, QTc prolongation, and multiple drug interactions due to CYP3A inhibition, especially with salmeterol-fluticasone, which, as the FAM protocol, is used frequently used to treat BOS. |
| Favipiravir | Preliminary results of a Japanese clinical trial showed that in COVID-19, compared with arbidol, favipiravir did not significantly improve the clinical recovery rate at day 7 [49]. | No definite role specifically in HCT. | Elevated serum uric acid has been associated with the use of favipiravir. |
| Herbal therapies: Nigella sativa | Potential demonstrated in molecular docking study [50]. | No role in HCT but has the propensity to cause prolonged QTc | Use should be strictly within the context of a clinical trial. |
| Avoid use in patients with lung GVHD receiving azithromycin. | |||
| Cytokine inhibitors | |||
| Eculizumab | Improvement in the COVID-19-associated ARDS/pneumonia in a case series [51]. | Treatment for HCT-associated microangiopathy (TTP). | Given its association with a serious increase in the risk of infection (meningococcus), use only in clinical trials. |
| Siltuximab | An improvement in the clinical condition was observed in 33% (7 of 21) of patients, 43% (9 of 21) of patients stabilized, as evidenced by no clinically relevant change in their condition, and 24% (5 of 21) experienced a worsening of their condition [43]. | Approved by the EMA and FDA for treatment of adults with HHV6-/HIV- multicentric Castleman's disease | Use only in the context of clinical trials. |
| Ruxolitinib | Possible role in hemophagocytic lymphohistiocytosis due to COVID-19 (trials started) | Approved for the treatment of steroid-refractory acute GVHD. | Risk of infection and thrombocytopenia with full-dose ruxolitinib. Thrombocytopenia and an ITP-like syndrome have been described in COVID-19 patients; thus, cautious use in clinical trials only is recommended. |
| Ibrutinib | Reported as perhaps beneficial for COVID-19 in a retrospective study [52]. | Approved therapy for chronic GVHD. | All patients on the reported study were already on ibrutinib. |
| Caution against using ibrutinib solely for COVID-19 infection in HCT recipients until trial data available | |||
| Immunosuppressives | |||
| Corticosteroids | Dexamethasone has been shown to improve mortality in COVID-19 patients [53]. | The primary treatment for both acute and chronic GVHD. | Judicious use of corticosteroids if needed. |
| IDSA recommendation only in cases of MAS or ARDS due to COVID-19 [54,55]. | Risk of osteonecrosis high in HCT recipients. | ||
| Mesenchymal stromal cells | Improved outcome in a single-arm trial of 7 patients [56]. | Approved treatment for acute GVHD in Canada, New Zealand, and Japan | Can be used in the context of clinical trials both autologous and allogeneic HCT recipients. |
| Multiple trials going on in ARDS due to COVID-19 | |||
| Interactions with other drugs | |||
| Voriconazole and posaconazole | No known role in COVID-19 | Commonly used in GVHD. | Azithromycin interaction with the CYP3A4 inducers. |
| CAR T cells (cryopreserved vs. fresh products) | No role in COVID-19 | Approved for post-transplantation relapse of ALL and NHL. | Post-CAR T cell infusion, any drug treatment should strictly be in the context of clinical trials. |
| CAR T cell therapy may be affected owing to the restricted availability of tocilizumab; therefore, consider CAR T cell therapy only for those with an urgent need. | |||
| General guidance from the CAR T cell consortium should be considered [9]. | |||
| ACE inhibitors | Hypothetically could increase the likelihood of acquiring SARS-CoV-2 by increasing ACE2 expression (virus-binding site) [57,58]. | No known role for treatment of any aspect of HCT. | Until data are available, do not stop ACE inhibitors in HCT recipients who are already on treatment. |
| Arbidol | A Chinese randomized controlled open-labeled trial demonstrated arbidol monotherapy had little benefit for mild/moderate COVID-19 infection [59]. | No definite role specifically in HCT. | Adverse events include diarrhea and nausea. |
BOS indicates bronchiolitis obliterans syndrome; MERS, Middle East respiratory syndrome; ACE: angiotensin-converting enzyme; MAS, macrophage activation syndrome; TTP, thrombotic thrombocytopenic purpura; EMA, European Medicines Agency; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma.