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COVID-19 Immunization in Oncology and Stem Cell Transplant Settings: Experts Provide Practical Guidance

Authors: Paul Moss, MD, PhD; Malgorzata Mikulska, MD, PhDFaculty and Disclosures


Activity Transcript

Paul Moss, MD, PhD: Hello. Welcome everybody. Thanks for joining us today at this live webinar on COVID Immunization in the Setting of Oncology and Stem Cell Transplantation Setting. As you'll see, we want today to give you practical guidance for your clinical practice. My name's Paul Moss, I'm professor of hematology at the University of Birmingham in the United Kingdom, and I'm joined with my colleague Malgorzata. Perhaps you'd like to introduce yourself?

Malgorzata Mikulska, MD, PhD: Yes. Hello everyone, I am Malgorzata Mikulska. I am infectious disease specialist with particular interest in immunocompromised patients, and among them, patients with hematological malignancies and stem cell transplant recipients. So welcome today.

Dr Moss: Thank you very much. So I think what we want you to get from this program over the next 40 minutes or so, we're going to discuss COVID-19 outcomes in patients with malignant diseases, including transplantation. We'll show you the clinical data for vaccines in patients with these conditions, and particularly we want to give information on guideline recommendations and practical points. But before we look at some of the impressive results from vaccination, let me take you back to those difficult times in the early days of the pandemic and look at what we were facing then, and I think we all have our clinical memories of that time in early 2020. This is a slide that shows patients with malignancy and their high rate of COVID-related mortality. This is particularly the 14-day case fatality rate. And if you look at the Y axis there, you can see 10, 20, 30% rates of mortality, and in the red bars is when the first wave happened.

If you look at the right-hand side of the screen there, those very high red bars, those are patients, as you can see, with multiple myeloma, leukemia, lymphoma. You can see already the risk that was seen in patients with hematological malignancies. And if you just go slightly to the left, you'll see lung cancer also standing out, and that's another condition that represents still quite a challenge. So that's what we were faced with and, of course, vaccinations have really transformed the picture.

So on the next slide is where we're particularly focusing on patients at high risk. This are some data that is from the United Kingdom actually where the government asked clinicians to try and identify patients with particularly high risk. This is patients with solid tumors and what was picked out was metastatic or locally advanced inoperable cancer, as you can see, lung cancer seems to be standing out, treatment type, people who are having chemotherapy PI3-kinase inhibitors or radiotherapy within 12 months, or patients who'd had operative resection within 3 months. So obviously cancer's a very common condition, unfortunately, but these seem to be the highest risk conditions. Then if you look within hematology, these were the areas that were picked out as particularly high risk, allogeneic stem cell transplant patients, particularly in the last 12 months, seem to be at high risk. All those patients who go on to have active graft-versus-host disease, because they need immune suppression.

And CAR T, of course, has transformed our practice, but that does also lead to immunosuppression. And you can see here that the recommendation was that those who'd received CAR T in the last 24 months were particularly high risk. I think there's been some debate about those times, 12 months, 24 months, and another thing that you might wish to take into account is the lymphocyte count. And if the lymphocyte count comes up to say 1 or more, that's giving you some confidence that there may be immune reconstitution. Hematological patients who've had systemic anti-cancer treatment were also particularly high risk, and those at the bottom, there are some blood cancers which are inherently immune suppressive no matter what the treatment. And you can see myeloma, chronic lymphocytic leukemia. And this is one of the reasons why patients with blood cancer are at such high risk. Now, vaccinations. Do vaccinations work in this group of immunocompromised patients? Yes, they absolutely do provide a lot of valuable protection.

Let's look at these data. This is quite an interesting slide because it was in the early days, you can look at that time there, January to September '21, the first nine months of vaccination. Now, it looks quite complicated, but we can certainly take you through this. On the top left you can see solid malignancy, over 8,000 patients. And then if you look on the right where it says 79, that is the vaccine effectiveness against hospitalization with 2 mRNA vaccine doses. So we're already getting nearly 80% protection against hospitalization just with 2 doses, and you'll see just below there compared with 85 with the Moderna 1273 and 72 with the BNT 162. Go down to hematological malignancies and those values are 74% protection, 85 with the Moderna, 62 with the Pfizer BioNTech. And then at the bottom, the organ and stem cell transplant patients, we've got a value of 59% protection against a hospitalization. Again, subgroup analysis showing a slight improvement with the Moderna 1273 at 70.

So what can we take from this? Initially, when we were looking for a vaccine for COVID, we were hoping for 50% protection, so we're getting much more than that. But these numbers are less than we're seeing in the general population and that's why we're here today to talk about how we can improve that further. Now then, how do vaccines work? Is it antibodies, T-cells? This is one interesting cohort where of hematology patients, started with 365, as you can see on the right, they had their 2 vaccines, and then the patients in green, seroconverted. But the patients in blue were those who didn't seroconvert and they went on to get the third vaccine, and you can see then some of those blues became green. But then what this group did was they looked at the rate of infection subsequently in this cohort and you can see that the patients who were seronegative had a higher rate of infection. This is what we call antibodies as a correlate of protection against COVID. And so I think the theme for today is we need to drive more people into seropositivity.

Dr Mikulska: So let me show you the seroconversion rates following primary vaccination in different patients with hematological malignancies. And actually, you see on the upper part the healthy controls, with almost 100% of seroconversion. You see solid cancers with a very good result of over 90% of seroconversion, and then you see hematological malignancies, which are significantly lower as far as the rate of seroconversion goes. However, they are still almost 70%, and I think that this is important to highlight that the rates are lower than in other patients, but they are still quite high. And you can see that those without hematological treatment get 80% rate of seroconversion, which is much, much higher than we expected and much higher than what we see also for other vaccines, think influenza.

And those who are on treatment, these are the patients with lower rate, which is 60% here, which is still good. However, these patients might require more attention. And if you go more into detail on the hematological diagnosis, let's look from the bottom to the up. So we have very good seroconversion rates in acute leukemia, and this is very positive information. Then slightly lower rates in myelodysplastic syndrome, in Hodgkin lymphoma, in multiple myeloma, still between 75 and 80%, which is excellent. And then there are 2 groups that have significantly lower seroconversion rates, and these are Non-Hodgkin Lymphoma and CLL patients. And these are patients who, due to treatments or intrinsically due to disease, frequently do not mount antibodies, so it's not surprising that antibody production has been impaired in these patients.

And this is my question to you. Well, according to current data, what is the effect of COVID-19 vaccination for a patient who has received anti-CD20 specific antibody within the previous 6 months? Do you think that vaccination is unlikely to provide clinical benefit and only prophylactic antibody therapy should be given? Do you think that the antibody response to the vaccine is likely to be less strong than seen in healthy donors and the T-cell response is also likely to be weaker anti-CD20 treatment? Or do you think that the antibody responds to the vaccine is likely to be comparable to what's seen in healthy donors, but the T-cell response is usually well maintained? Or the antibody responses to the vaccine is likely to be less strong than seen in healthy donors, but T-cell response is well maintained? The T-cell response is usually well maintained, and this is one of the reasons that we say that in these patients, the fact that they did not seroconvert does not mean that they did not get any benefit from the vaccination. And I think it's very important to highlight this point because in the beginning, people were saying what's the use of vaccinating them if you don't get the response? And there is the reason to vaccinate them. And for this reason, I will show you these data, if I can get to another slide. Sorry. No. Okay, sorry. This is the slide that I was looking for.

So I like that there are many different studies on this topic. I like this one because of the colors that are immediate. So you can see here that these are the responses to mRNA vaccine in patients with hematological malignancies and stem cell transplant recipients. And the pink one is a good response, both cellular and humoral response present. The violet one is no response, no cellular and no humoral. But what we are focusing on now are those that are blue bars, and blue bars are the patients who did not develop antibodies but did develop cellular response to the vaccine. And as you can see, these bars are particularly pronounced in lymphoid malignancies and in patients treated with anti-CD20 antibodies. So that shows that even if there is no serological response, between cellular response with or without antibodies, we are covering almost 80% of the vaccinated population, which is excellent news. And have a look at these bars that they show that even in transplant recipients with different immunity, still the pink bars, which is both responses present, are more than 50%.

And well it shows clearly in the huge population data, and this is from the EPICOVIDEHA European study, you can see that the mortality in hematology patients in the pre-vaccine era was as high as 40% with survival that the lower line is at 60%. However, in the vaccine era, and we are talking from January 2021 to March 2022, the mortality was less than 20%, and this is extremely important. It's still higher than in the general population, but it's a significant improvement. However, what happens, we get our patient a vaccine and we know that the antibody levels will decrease over time. We have seen the waning of immune protection in healthy subjects, we have seen it in cancer patients. And you can see here on the left, the red dots are showing that in the cancer cohort, maybe because the immunity is still somehow impaired, this waning, this decrease on the antibodies is more pronounced. So they do need to do something in order not to lose all their antibodies.

And if you can look at the right side of the slide, you will see that the longer the bar, the more significant decrease in the antibodies occurred. And leukemia and lymphoma patients, the far right in green, are those that have the higher loss of the antibodies. So what should we do? We know that there is a way to increase the antibody rate and to increase seroconversion rate, and a booster dose, the third dose, has been shown benefit in increasing the rate of seropositivity in patients with hematological malignancies. Here you have one meta-analysis, but there are others as well showing consistently that the rate of seronegative patients decreases with the third dose. However, what happened as well, you can see here on the left that we have solid and hematological malignancy patients, and they had significantly lower antibody levels before the third dose than after the third dose.

So the increase, if you look at the numbers, they are more than twice higher after the booster dose. However, days or weeks after the third dose will have the same story, the antibody levels will decrease. Their partial immunity will remain, but the antibody levels across all the categories of hematological malignancies have been shown to decrease. So what we do? We make them increase once again. And this increase can be given by a fourth dose of the vaccine. Here, there are data for mRNA fourth dose vaccine and you can see here that both in solid cancer patients and in hematological cancer patients, the rates increased significantly. And if you see on the right, the rate of those who are seronegative was almost zero in solid cancer patients and was still significantly reduced to less than 20% in hematological malignancy patients. So these are important data showing that in these populations, the boosting really increases the antibody levels.

Dr Moss: Thank you very much. So I think what we're saying here is that immunocompromised patients need additional vaccine doses and we're trying to drive them towards seropositivity. What's the evidence for that in terms of protection? I think this is a very nice study actually from Leonard Lee and colleagues from the UK, and what he did was look at cross-sectional antibody testing in the population and then compared patients with cancer with the general population. And look at the time period, it's quite interesting, September '21, which was really a Delta time, through to March '22, so it incorporates the Omicron wave as well. And interestingly, if you look at the general population of the people who had tests, seronegativity was less than 1 in 1,000. Really fascinating how many people had by then, either through vaccines or infection, got some level of seroconversion. But look at this population of cancer patients, over three and a half thousand patients, so statistically strong.

On the right, you can see 2 groups where there are lower levels of antibodies and those are again the blood cancers, leukemia, lymphoma, and myeloma. And the seronegativity despite 3 vaccine doses here was around 14%. For the whole cancer population in general, seronegativity was still around just under 5%, so you can see the difference compared with the general population. Now, what about protection against infection and hospitalization? Here are the data, and on the left is the relationship between the antibody level, the titer on the X axis, so as you can see as you go right, higher antibody levels, and on the Y axis, the percentage of infections, the breakthrough infections. And again, right at the top left, lymphoma, leukemia, low antibodies and higher rates of breakthrough. Overall, there was a 3-fold odds ratio of infection for people who were seronegative. On the right, hospitalization. And here, the same sort of picture with those type of disorders in the top left, but the odds ratio here was even higher, 6 and a half for patients who were seronegative cancer patients, their risk of hospitalization. So we really do need to get that improved.

As Malgorzata was saying, this is where we really need fourth vaccine doses and beyond, in fact. This is just one of many slides that we could have chosen to show you. This shows the inhibition of neutralization of fourth dose in patients with multiple myeloma, and you can see in the blue columns on the left is before the fourth dose and on the right is after. And you can see they've specifically picked out patients who had CD38 therapy, BCMA targeted therapy, or others. And you'll see both blue columns are shifting up. And remember what we're trying to do with booster vaccines, there's a number of things, we're trying to increase the antibody titer and to maintain it to seroconvert more patients, but also to improve the quality of the antibodies so that it has better neutralization of viral variants. And this is something that we're seeing in this slide, this percentage inhibition of viral replication. The subgroup of BCMA, you can see there, showed low inhibition, but that was a really small group and I don't think that was statistically particularly notable, but shows the power of the fourth vaccine.

Now, we haven't talked a lot today about T-cells, but here are some data in stem cell transplant patients and they show again the booster T-cells. On the left, we're seeing measurement of T-cell responses and you'll see the bottom left is spike, the vaccine response. You'll see healthy donors in red and they're making T-cells to vaccination. Patients just after 3 vaccines, you can see in black, they have low responses but are in blue. The fourth vaccine dose is bringing them up and it's bringing them up statistically to the same level as healthy donors. So although patients with transplants do have impaired T-cell function, the vaccines can help here as well. On the right is an interesting little graph looking at the time interval since the last vaccination and the T-cell response. So as time goes on, maybe the T-cell response is coming down. Is that T-cell waning? Difficult to say, but it's certainly possible. Certainly, T-cells can live for a very long time and, of course, this is dealing with SARS-CoV-2, but the SARS-CoV-1 virus from 20 years ago, people had T-cells for 18 years, so we're hopeful that T-cell memory will be maintained.

Dr Mikulska: It's so true about hospital admissions. Even in our clinical practice, those few patients that are admitted for COVID pneumonia now during the Omicron phase and after the vaccination, these are Non-Hodgkin lymphoma and chronic lymphoid leukemia patients. Because people with acute leukemia, even if they get COVID-19, they do not progress usually to severe disease, so these are our at risk populations. So while we are stating the benefits of the fourth dose of mRNA vaccines, we should look also at the safety. And here, you can see any local injection site reaction, any systemic reaction, any health impact, being unable to perform daily activities, go to school or to work, or need medical care.

And you can see that the third and fourth dose do not result in higher percentage of negative side effects compared with the first 2 doses. And I think that local injection reaction is something that we observe very commonly. However, serious complications are very, very infrequent and they should be also judged against the potential of COVID-19 infection to cause any harm. So I think that in this population, the lack of safety of vaccines should not be our concern because it has not been shown and it really offsets the benefits. So this brings me to guideline slides, which are a little bit busy, but we wanted to show them just in full to then pinpoint certain aspects.

And you can see here, the upper left part is the most frequent situation. So currently these are CDC, the US guidelines, however they were designed specifically for people who are moderately or severely immunocompromised and they are quite easy to look up, so I think it's worth mentioning that you can come back to them even later if you have some doubts. And you can see here that for people over 12 years of age, we have now the recommendation on 3 not 2 primary doses of mRNA vaccine. The first 2 doses with the interval of 3 to 4 weeks, the second and fourth of at least 4 weeks. And it's also recommended that those who did not receive the third primary dose, they should receive the third primary dose, and then at least 2 months later a bivalent mRNA booster is recommended. And the scheme changes a little bit for other vaccines, but this is the main point.

Dr Moss: Yeah, we talked about this earlier, didn't we, Malgorzata? I mean that top left is quite interesting to me because certainly in the UK, for instance, the immune-suppressed populations now are typically recommended to have had 6 vaccines. So we would follow those 3 primary vaccines, but where it says at least 2 months, we gave 2 booster vaccines of the original vaccine and then now that bivalent. So just where it says at least 2 months, we probably would've been able to fit in 2 more vaccine doses. So that was of interest to me.

Dr Mikulska: And we did fit them. And the recommendations are that still at least 2 months after your boosters, you can get bivalent one as an additional dose and it would be fifth or even 6 dose. So I think it's important to remember that in the meantime, we were giving the patients the boosters with the efficacy that we showed. Well, the bottom part of this slide has become more obsolete in the last weeks or month and something because these are the recommendations on the passive immunization. Pre-exposure prophylaxis with multiple antibodies, long-lasting, approved for this indication. And here, the slide specified the timing. So if you vaccinated your patient, you need to wait at least 2 weeks to give him or her the pre-exposure prophylaxis. But once you give the pre-exposure prophylaxis, you can vaccinate the patient almost immediately because it will not interfere with the efficacy of the vaccine.

However, we know that with the currently circulating variants, even these monoclonal antibodies have lost most or all of their efficacy. We are hopeful that we'll get another ones since many of them have been developed, but we are still waiting for them. So another guideline that you can look up are NCCN guidelines, which actually are very interesting to look at as far as vaccination timing is concerned because sometimes it's difficult to fit in the vaccine in a patient who's receiving chemotherapy. And here, you have the recommendations that in patients after stem cell transplant therapy, vaccination should start at least 3 months later. In those who are receiving intensive cytotoxic chemotherapy for hematological malignancies, you should probably delay until the resolution of neutropenia. However, in those who are not expected to recover, vaccinate them. You cannot do harm. But if you do not vaccinate them, you will not give them the benefit. And I think this is an important message that we still may vaccinate these patients and expect some benefit.

And for major surgery for solid tumors, while we do not give it on the same day of surgery, just separate the date of surgery from vaccination by at least couple of days, or longer for complicated surgery or for transplant, for example, solid organ transplant. However, do not wait too long because there is no reason to postpone vaccination. And the European guidelines from European Conference on Infections in Leukemia have provided very detailed recommendations both for patients without transplant but with hematological malignancy and after transplant. And actually, they stated that even patients with previous COVID-19 should be vaccinated with a full primary schedule, that people should be informed about the ongoing risk of COVID-19 and maintain other protective measures. This is very important, particularly today when SARS-CoV-2 is still circulating a lot in the community. So masking, distancing, hygiene.

Household contacts, of course, should be up-to-date with the vaccination, as for any other vaccine preventable disease like influenza. And treatment with any monoclonal antibodies should not prevent us from giving the vaccination. And then if someone has not yet received the primary vaccination schedule, now we know that it should be 3 doses. Also for children that are the group, for example, that might come to the age of being vaccinated as recommended by international and national guidelines, boosters should be considered at least 3 months after the third dose, and people who were vaccinated either during chemotherapy or before, we must check for antibody titers to see if they should be revaccinated quickly or we can also opt for giving the necessary boosters. And even if it's not graded, it's very important to know that COVID vaccinations should not in any way delay the treatment of the underlying disease.

Going to transplant recipients, well 3 months time point for the initiation or revaccinated of these patients still stands if there is high ongoing transmission in the community, 6 months the efficacy might be higher and is the acceptable time point if the circulation in the community is lower. And it's important to know that there is some minor risk of worsening or eliciting GVHD, however it has not been considered a contraindication to vaccination, but only as a factor to influence the timing of the vaccination after transplant. And one of the last things that we need still know as caring physicians, but we also need to transmit it to the patients, is that even in the times of boosters and Omicron, when we look at risk factors for dying from COVID-19 after receiving the booster, cancer, hematological malignancy, bone marrow transplant, and, among solid cancers, lung cancer are those categories that are still at risk for dying. And I think this is important to highlight.

Dr Mikulska: Thanks, Malgorzata. Right, we're right at the end really, and I want to get some time for questions if I may, but these are hopefully some of the points that have come out in the last half an hour, the timing of vaccination, considering a treatment, number of vaccine doses, which is now up to 5 or 6 in many cases, and of course, the use of pre-exposure prophylaxis strategies, and we'll probably touch on those in some of the questions.

I think one thing we should just mention as we come to a close is vaccination's the backbone of protection for this population. But of course, antiviral drugs, have a place when infections occur, don't they? And we're seeing less monoclonal antibody use in the last 30 seconds or so. Not used so much, certainly.

Dr Mikulska: Monoclonal antibodies, most of them, if not all, lost their efficacy against the currently circulating viruses. However, the early diagnosis and early treatment with antivirals is another very effective method to reduce the mortality. And I think it should be given in a junction, of course, to full vaccination.

Dr Moss: We really must stop there. I'm sure we'll get new monoclonals coming through, science has been great, but we will have to stop there. I hope you've enjoyed that session and taken home some learning points. I've certainly learned a few things today and really enjoyed it. So thank you very much for joining us today.

Dr Mikulska: Thank you

This transcript has not been copyedited.

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