Convalescent plasma for COVID-19 in oncohematological patients: a call for revision of the European Conference on Infections in Leukemia-9 (ECIL-9) guidelines

The recommendations for the management of COVID-19 in patients with hematological malignancies or hematopoietic cell transplantation, from the 2021 European Conference on Infections in Leukaemia (ECIL 9) were published online in Leukemia on April 29, 2022 [1]. This conference was held virtually on September 2021 and we worry some of the recommendations are out of date. Keeping guidelines updated represents a formidable challenge in a rapidly evolving pandemic, but is nevertheless fundamental to avoid misuse of resources.

The prerequisite “when monoclonal antibodies are not available”, for recommending COVID19 convalescent plasma (CCP) use, and the sentence “sotrovimab is the only anti-S MAb to retain activity against the recent Omicron variant” suggest that the manuscript was drafted before the onset of the Omicron BA.2 and BA.5 variant waves, which dominated the landscape and are resistant to any monoclonal antibody (mAb) authorized by the EMA so far. In the USA, the FDA has withdrawn the usage of casirivimab+imdevimab (since December 2021), sotrovimab (since March 2022) [2], and bebtelovimab (since December 2022)

For prophylaxis, cilgavimab+tixagevimab is the only mAb approved by EMA, on the basis of randomized controlled trials (RCT) completed during the Delta variant wave: unfortunately the tixagevimab component of the cocktail was ineffective in vitro against BA.2 and BA.5, and real-world evidences suggest that there could be dosing failure [3] leading to a high incidence of breakthrough infections [4]. Overall, it has been clearly demonstrated that the risk of immune escape with each single mAb is very high, especially among immunosuppressed patients who harbor persistent infections with high viral load [5], [6]. Furthermore, BQ.1.1.* and XBB.* are fully resistant to cilgavimab+tixagevimab.

As stated by the authors, seronegativity (as opposed to earliness) is the key driver for the success of antibody-based treatments in COVID-19 in immunocompromised patients. As such, there is huge rationale for CCP in B-cell depleted patients, and we can't understand why in Table 2 CCP has been appropriately recommended by ECIL-9 until seronegativity persists in mild COVID-19 cases, but instead only within 72 hours from onset of symptoms in moderate COVID-19, since numerous reports document responses in patients even after weeks to months of disease [7]. For the same reasons, patients with critical COVID-19, manifest similar (minor) benefits from either casirivimab+imdevimab (now totally useless against Omicron) and CCP (which is instead not recommended at all in the Table). Of interest, there are now reports that CCP can halves the risk ratio for mortality in immunocompromised patients [8] and rescue the ones who have failed under mAbs [9], but the contrary situation has never been published, confirming the superior potential of polyclonal preparations . We note in vitro data showing CCP from donors who have been vaccinated and recovered from infection is extremely high titer and shows neutralizing activity against emerging variants of concern [10]

Concerns also currently exist with oral small-chemical antivirals (specifically, viral and clinical rebounds for nirmatrelvir [11] and low efficacy and mutagenicity for molnupiravir [12]), for which repeated or chronic exposure has not been formally investigated in immunocompromised patients yet.

Nowadays CCP can be easily collected by convalescent vaccinees that were already regular donors, who have far higher levels of neutralizing antibodies than CCP collected in the before-vaccine era. It works against BQ.1.1.* and XBB.1.* [13], is relatively safe, has fewer contraindications than small-chemical antivirals, and, in addition to polyclonal IgG, includes IgM and IgA (which retain much of the neutralization capability on respiratory mucosae). Furthermore, CCP could be the only antiviral affordable to low-and-middle income countries. Hence, we feel that evidences for usage should be ranked equal to or higher to other antivirals.

We hope that, on the basis of such evidence, ECIL-9 will soon revise its recommendations to remove treatments that are no longer effective (e.g., sotrovimab and Evusheld) and by increasing the level of supportive evidence for CCP. Furthermore, to date no head-to-head randomized controlled trial has been even run in immunocompetent COVID19 patients, but it could be time to launch it for immunosuppressed oncohematological patients in the era of Omicron and its likely follow up variants. Contemporary updates to the guidelines will continue to be important given the suboptimal antibody responses to COVID-19 vaccination and boosters among patients with hematological malignancies or hematopoietic stem cell transplant recipients.

Author contributions

D.F. wrote the first draft. A.C., M.J. and J.S. revised the manuscript.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

A.C. was an investigator in the CSSC-004 RCT of CCP. D.F. was an investigator in the TSUNAMI RCT of CCP. M.J. and J.S. were investigators in the US Expanded Access Program of CCP.