Mortality Rate Associated With COVID-19 Breakthrough Cases Remains High in Hematologic Malignancies

Although mortality rates in patients with hematologic cancers who develop breakthrough COVID-19 cases after vaccination are high, there has been a significant decrease in incidence since vaccines have become available.

Although mortality rates in patients with hematologic cancers who develop breakthrough COVID-19 cases after vaccination are high, there has been a significant decrease in incidence since vaccines have become available, according to preliminary data from the EPICOVIDEHA trial (NCT04733729) published in Blood.1

Results from the first study to report on post-COVID–19 vaccination cases in this population showed that among 3801 patients included in the study, 113 developed COVID-19 after vaccination. Of those patients, 79 experienced severe or critical COVID-19 infection, 75 were hospitalized, A total of 14 (12.4%) patients died during the study. COVID-19 was deemed the primary or secondary cause of death for all but 1 patient. Prior to the availability of vaccines, mortality rates for those with hematologic cancers ranged from 30% to 50%.

“Before vaccination, if our patients with hematologic malignancies developed COVID-19, they died in a lot of cases,” study author Livio Pagano, MD, of the Università Cattolica del Sacro Cuore in Italy, said in press release.2 “With these preliminary data, we showed that vaccination is not able to completely protect, but surely it has a strong role in reducing the mortality for COVID-19 for people with blood cancers.”

In April 2020, the European Hematologic Society – Infectious Disease Working Party launched a web registry to collect data on patients with hematologic cancers who developed COVID-19 infections in an effort to understand epidemiology, risk factors, and mortality rates. Among 3801 cases collected in the registry, the observed mortality rate was 31%.

After the first COVID-19 vaccines became available in Europe in December 2020, the registry began collecting additional data in January 2021 on adult, fully or partially vaccinated patients with hematologic cancers who developed COVID-19. Investigators sought to assess the efficacy of the vaccines in the patient population, as well as potentially identify categories of patients who may be less protected by vaccination.

Participating institutions were tasked with collecting data through the EPICOVIDEHA electronic case report from January 2021 through December 2021. Data collected includes information on underlying conditions before COVID-19 infection, hematologic cancer status and management before infection, vaccination status, infection details, and mortality.

Patients examined were considered fully vaccinated if they received their final dose of the COVID-19 vaccine 14 days or more before the onset of symptoms and/or had a positive PCR test.

Of the 113 patients with hematologic cancers who developed COVID-19 after vaccination, a majority were 50 years old or older (85.8%) and male (61.1%). A majority of patients had lymphoproliferative malignancies including chronic lymphoid leukemia (24.6%), non-Hodgkin lymphoma (31.9%), acute lymphoblastic leukemia (2.5%), Hodgkin’s lymphoma (3.5%), and multiple myeloma (17.7%). Moreover, 68.1% of patients were receiving active treatment for their hematologic cancer at the time of COVID-19 infection or had received treatment within the previous 3 months.

Most patients examined received an mRNA vaccine (87.6%), and the median time from last vaccine dose to COVID-19 infection was 64 days (range, 33.5-108). Seventy-seven percent of patients were considered fully vaccinated and 23% received at least 1 dose of the vaccine.

Post-vaccine immunoglobulin G levels against the SARS-CoV-2 spike protein were analyzed in 35.4% of fully vaccinated patients 2 to 4 weeks after their final vaccine dose. Only 32.5% mounted an antibody response to vaccine and 67.5% were considered non-responders.

Additional data showed that there was no statistical difference in mortality among patients who were fully and partially vaccinated (15.4% vs 11.5%; P = .734), or between vaccine responders and non-responders (13.3% vs 15.6%; P = 1). Furthermore, age was the only factor independently related to risk of mortality in multivariable analysis (HR, 1.053; 95% C, 1.004-1.105; P = .035).

Moreover, 71.4% (10/14) of patients who died had underlying lymphoproliferative malignancies. Study authors noted this did not include acute myeloid leukemia, which in previous studies was associated with the highest mortality rates in non-vaccinated patients.

“The overall mortality observed in our patients, although lower than in the pre-vaccination period (31%), remained high (12.4%),” study authors wrote. “This percentage, on one hand remains quite worrying for hematologists, but, on the other hand, should be interpretated as a significant achievement following the spread of vaccination programs around the world.”


  1. Pagano L, Salmanton-García J, Marchesi F, et al. COVID-19 in vaccinated adult patients with hematological malignancies. Preliminary results from EPICOVIDEHA. Blood. Published online November 8, 2021. doi:10.1182/blood.2021014124
  2. Study finds COVID-19 breakthrough cases can be severe for people with blood cancers. News release. American Society of Hematology. Published November 8, 2021. Accessed November 11, 2021.