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Any medical conference this year cannot avoid discussion of COVID-19 and EHA was no different. A study was conducted by Dr Rom Ram at the Tel Aviv Sourasky medical centre in Israel on the safety and effectiveness of the Pfizer-BioNTech vaccine in patients after allogeneic stem cell transplants (a transplant involving a donor) and CD19-based CAR-T therapy. The study was relatively small, with 66 transplant patients and 14 CAR-T patients included but is the first that we are aware of published on COVID vaccines in this particular group of patients.
The study found that overall, the vaccine is safe and negative side-effects were rare and mild. Only 5% of the patients in the study developed side effects, including blood counts dropping temporarily and any graft versus host disease getting worse, but the doctors were able to control these for the affected patients.
There are two different types of adaptive immune response which allow the body to defend itself against a virus like COVID-19. The first is the antibody response, where you B cells make antibodies in response to detecting the virus. The antibodies mark the COVID-19 cell for destruction by the immune system. The second is cellular response or cell-mediated immunity which instead involves T-cells and other cells that can directly destroy COVID-19 without antibodies.
In this study the researchers found the antibody response was surprisingly high for patients who had undergone a transplant, with 82% showing a positive response. This number increased to a total of 86% when also including those who had a positive cellular response. Any response, either T cell or antibody, is likely to give protection but we do not yet know which is more important. However, in patients who had received CAR-T therapy only 36% showed a humoral antibody response. However, this figure rose to a promising 79% when cellular response was taken into account. The researchers found that the response was affected by the time from the treatment: patients who had the Pfizer COVID-19 vaccine shortly after the infusion had less response to the vaccine. This shows that it is important to time the vaccine correctly; CAR-T and stem cell transplants involve removing some or all of the person’s immune system and replacing it with a new one or new parts, and this study showed that you should wait for the immune system to recover before you have the vaccine following these therapies.
Every year, EHA holds a set of talks known as the Patient Advocacy Track. This is a space for patient organisations to communicate with researchers and doctors about the biggest issues facing patients. One point of discussion this year was about the barriers and bureaucracy involved in running clinical trials. The current system to set up and run clinical trials means that 60% of capacity in organisation that used to be a space of freedom to operate research is now invested in paperwork. One speaker from the Lymphoma Coalition, Natacha Bolanos, set out why this needs to change.
The goal of the clinical trial regulation is to create a favourable environment for conducting clinical trials in Europe, with the highest standards of safety for participants and increased transparency of trial information. Unfortunately, more action is needed to bring patient interests to the centre of trial design. Clinical research by nature tries to do a difficult balance between issues such as efficacy, efficiency and safety. The speaker spoke about how sometimes the problem is that safety is overdone; e.g. there is a lot of paperwork that does not add value to the patients, clinicians or the scientists data as though it is equally important as the research itself for the patient’s benefits.
Additionally, the speaker felt that currently massive amounts of unclassified and unprocessed information is collected in trials and each item of data generates burden and cost. The challenge is whether that data is valuable or not and to understand this we must ask if it is proportional to the costs and if it is processed efficiently. For example, the speaker outlines a Canadian study that found that only 18% of data collected during cancer clinical trials were reported in future publications.
Researchers now receive a significant amount of information on side effects that are already well-known. So how can we actually see where the risks are for the patient through the immense noise of too much data? The speaker felt that the current process makes poor use of the limited time in which decisions have to be made. That time should be better invested in patient care.
The speaker also spoke about bureaucracy form the patient perspective. Joining a trial comes with a lot of paperwork, often documents that absolve others of the consequences of joining are trial, where there might be unknown risks. The complex legal vocabulary used means that patients might no longer truly understand what they are getting involved with.
The speaker shared a recent study published on the assessment of length and readability of informed consent documents for Covid-19 vaccine trials. The findings suggest that existing Covid-19 vaccine informed consent documents were too long, difficult to read, and exceeded grade 9 in language complexity, requiring a average of 35 mins to read the entire document. The speaker felt we must go back to the basics in informed consent and help patients and clinicians to properly share decision making by delivering understandable and relevant information to patients.
Headlines in CLL at this year’s EHA conference focused heavily on the Bruton’s tyrosine kinase inhibitors (BTKi). BTKi inhibit the enzyme BTK, which is a crucial part of how signals are communicated within the CLL tumour cell to help it survive. BTKi block this signalling and trigger cell death (apoptosis).
The results of several trial comparing BTKi’s with each other became available at the conference. Studies that directly compare these treatment will be important for making the treatment available on the NHS, as bodies’ like the National Institute of Health and Care Excellence (NICE) will want to see how the newer BTKi’s improve on previous ones before they are approved. Also, the first generation BTKis are not perfect; ibrutinib comes with many side effects. It is hoped that future BTKis will improve on this.
One study presented was the ALPINE study, a phase 3 clinical trial comparing ibrutinib, which has been in use for several years in the UK, with zanubrutinib which is not currently available. People on zanubrutinib were more likely to respond and were likely to live for longer without progressing (measured by progression free survival). Zanubrutinib showed an increase in neutropenia compared to ibrutinib, but fewer other side effects.
Another exciting development is the release of data from the early clinical trials of third generation BTKi therapies such as pirtobrutinib. You may also know this as Loxo-305. This BTKi works in a different way to previous ones, in that it binds to the BTK protein differently. It is hoped that this means it will work for people resistant to other BTKis and have different and/or fewer side effects. The BRUIN trial is a very early study that was designed to work out the best dose, rather than compare pirtobrutinib with other treatments. However, 83/88 people who had pirtobrutinib remained on the treatment and 63% responded to the treatment, so the data looks promising.
In addition to BTKi inhibitors being discuss, Professor Peter Hillmen from the University of Leeds helped to provide an overview of clinical trials data to explain treatment advances in CLL, the new treatment landscape and pros and cons of different treatment choices when selecting and sequencing treatment of CLL. His presentation, “Standard- vs high-risk chronic lymphocytic Leukaemia in the novel agent era” was of particular interest. Here are Professor Hillmen’s key points:
- Many trials of BTKis have now been conducted showing these are effective option for first treatments for CLL. Professor Hillman stated that patients had better outcomes on these than on chemo-immunotherapies such as FCR. The combination of venetoclax and obinutuzumab is also more effective than chemo immunotherapies. However, there is a subset of patients, those with mutated IGHV genes, that do really well on FCR. This shows the importance of working out the best treatment for individuals.
- The data on fixed duration CLL therapies, such as having venetoclax for two years, is now maturing. What is now known is that how deep a remission you get, as measured by the absence of measurable residual disease (MRD) in the body, is important for predicting those who will stay in remission the longest. Minimal residual disease is the presence of small, but measurable, numbers of leukaemia cells in the blood when the patient is in a remission. Those patients with lower negative levels of minimal residual disease do better than patients with positive minimal residual disease levels.
- Interestingly, combining non-chemotherapy agents, like ibrutinib and venetoclax together, are achieving the greatest responses with the highest number of patients achieving undetectable levels of minimal residual disease. Clinical trials of this combination are showing an improvement in response all types of patients, but importantly, a response in 75% of patients who are considered at high risk of relapse. This is better than responses to FCR for this group who are difficult to treat.
Scientific knowledge has now improved dramatically to aid more effective treatment of all CLL patients either with fixed duration or continuous therapy treatments, many are now approved by the NHS or available in clinical trial. Mature data and the CLL clinical community are now expressing clearly there is a limited, if any place for immunochemotherapy use to treat CLL today.
This has enabled a safer and more individualised approach to treatment of CLL patients. But choice does come with difficulties for the patient and the clinician.
Understanding the complexity of the advantages, disadvantages and what treatments are appropriate to treat an individual patient are complex. Treatment advances have aided consideration of patients’ lifestyle preferences and wishes when a treatment is chosen today to aid shared decision making at the point of treatment.