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The SARS-CoV-2 pandemic has changed the world over the last year and impacted almost every part of our lives. In particular, patients with hematologic malignancies have been significantly affected by this crisis at every stage of their treatment. Delays in diagnosis and increased waiting times for transplants and therapy have become common occurrences. Patients with hematologic malignancies are also more likely to suffer from severe COVID-19, leading to a greater mortality rate. A recent meta-analysis of 3,377 patients with hematologic malignancies and COVID-19 showed a mortality rate of 34% (95% CI, 28−39).1
During the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), two speakers reflected on the past year, living and working with COVID-19, and discussed the specific effect this has had on transplant patients and their families.
Steve Pergam, Fred Hutchinson Cancer Research Center, Seattle, US, discussed vaccination in patients receiving hematopoietic stem cell transplants (HSCTs) and cellular therapy.2
Vaccination has been heralded as the way out of the pandemic, but for transplant recipients, this poses difficulties. HSCT recipients have slowly recovering immune systems that may not be able to mount an efficient response to challenge by the vaccine.
There is also the question of the timing of vaccination following transplantation. Certain centers rely on CD4 counts to identify the optimal time to vaccinate. Others reference the timing used for other vaccinations, such as influenza. However, there is controversy with the European and US guidelines recommending different times (3 vs 6 months, respectively). Patients may receive autologous (auto)-HSCT or allogeneic (allo)-HSCT, and there are not yet enough data to conclude whether these two transplant types would correspond with the same vaccination timelines for patients.
Transplant-eligible patients are a heterogeneous group with comorbidities, graft-versus-host disease (GvHD), and immunosuppressants complicating the situation. As a result of these issues, transplant patients are not included in vaccine trials, so there are little data to guide vaccination recommendations for this high-risk group.
A number of different approaches can be used to inform decisions about when to vaccinate patients undergoing transplant. Results from established vaccines, such as the influenza vaccine, have been assessed in this patient setting. Compared with healthy individuals, influenza vaccine responses in HSCT patients have been less robust, although improved responses can be achieved using high doses or booster shots.
While the recommendations advise waiting at least 3 months after transplant, whether earlier vaccination provides any protection is an unanswered question. While data are limited, work has been done with pneumococcal vaccines in patients who had received an allo-HSCT. The results showed that immunoglobulin G levels after the first dose were variable, with some patients able to mount a good immune response while others responded poorly to challenge. Subsequent booster doses improved this response. Following a 6-month interval between third and fourth boosters, antibody titers did decrease somewhat, but another round of booster vaccinations overcame this drop.
A second study performed with the influenza vaccine in a randomized controlled trial showed that while more patients seroconvert when vaccinated at >6 months following allo-HSCT, 40% of them seroconverted when vaccinated earlier than 6 months. Therefore, a proportion of patients may benefit from early vaccination.3
Patients may also lose pre-existing protection from vaccinations received prior to transplantation. There is evidence in allo-HSCT patients that measles protection can be lost, whereas this is less common in patients following chimeric antigen receptor (CAR) T-cell therapy.
A limited number of patients with cancer and/or undergoing transplant were included in the major COVID-19 vaccine trials.
For the Pfizer vaccine, 1,395 (3.7%) of the clinical trial participants were patients with cancer; however, none were receiving active chemotherapy or immunosuppressants and, therefore, may be long-term cancer survivors.
The Janssen/Johnson & Johnson vaccine trials only included 226 (0.5%) patients with cancer but did include an additional 79 (0.2%) immunocompromised patients following a blood transfusion. Further results from these groups have not been released.
Mette Hazenberg, Amsterdam UMC, Amsterdam, NL, spoke about the situation in the Netherlands for transplant-eligible patients during the COVID-19 pandemic.3
As was the case in many countries, cell therapy and HSCTs were postponed during the first wave of infections. In addition, anxiety regarding going to healthcare providers due to the risk of infection also led to a decrease in patients diagnosed with hematologic malignancies. When the second wave of infection arrived, the Dutch healthcare systems had adapted with the introduction of preadmission testing and the use of cryopreserved transplantations to allow HSCTs to resume.
Cryopreserved transplants have been analyzed to assess if there are any deleterious effects of storing samples in this way. A recent paper by Maurer et al. found that engraftment was delayed when measured at 30 and 100 days after transplantation.4 So far, no sequelae have been recorded from this procedure, but further data are required.
While prioritizing patients who have received a transplant seems a logical conclusion from the data discussed, it might be challenged by the strength of response to a COVID-19 vaccine in this group. Patients who receive an auto-HSCT will have depleted T- and B-cell populations, and allo-HSCT patients may also be on immunosuppressants.
A study called COBRA-KAI (2021-001072-41) is being set up in the Netherlands to investigate the efficacy of COVID-19 vaccines in 850 patients with hematologic malignancies, including patients receiving auto- and allo-HSCT within the last 6 months. Patients with chronic GvHD who use at least two immunosuppressants will also be included in this trial, as well as those receiving CD19 CAR T-cell therapy.
This study aims to:
In the current COVID-19 scenario, there is limited information available from the traditional sources that would inform recommendations in this group, such as clinical trial data, prospective non-randomized data, other groups with immunosuppression, or similar vaccines. Therefore, vaccination recommendations must rely on information from other vaccines and expertise from medical communities.
Current guidelines from the National Comprehensive Cancer Network (NCCN), American Society for Transplantation and Cellular Therapy (ASTCT), and EBMT all recommend waiting until 3 months after allo-/auto-HSCT to receive a COVID-19 vaccination.
Exceptions to this advice include:
These recommendations were made based on data from the influenza vaccine.
The COVID-19 pandemic has challenged healthcare services and individuals worldwide, especially patients with hematologic malignancies. The rapidity of SARS-CoV-2 spread and the novel nature of the resulting disease has reduced the amount of data available to make recommendations. However, the scientific community has risen to the challenge, and great work is being done to explore how patients receiving transplant respond to vaccination. Current recommendations suggest patients undergoing HSCT wait at least 3 months after transplant to get vaccinated, but this advice may be updated following the collection of further data, such as from the COBRA-KAI trial.
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