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First CAR-NK trial in relapsed/refractory AML patients
CAR-T therapy has demonstrated great success in acute lymphoblastic leukaemia (ALL) and lymphoma patients. It is a type of therapy that involves editing someone’s cells to make them work more effectively at fighting cancer. Whilst it is primarily the patient’s own cells being used, there are now also trials using other people’s cells – however, at present, no such therapy exists for patients with acute myeloid leukaemia (AML).
Currently, patients with AML who have relapsed or are refractory (not responding) to treatment (R/R) are in need of better treatment options that are more effective. Dr Huang from China reported the results of the first-in-human trial use of CAR-NK cells in patients with R/R AML.
Five patients with R/R AML were treated with CAR NK (natural killer) cells modified to attach to AML cells with a CD33 protein attached to it. CD33 is commonly found on AML cells, making it a good treatment target. The NK cells, which are a type of white blood cell, were collected from umbilical cord blood, manufactured into CAR NK cells and stored – creating an “off the shelf”, readily available product that could be stored until needed. The initial response to treatment was promising, with the best responses observed in patients with lower disease burden (fewer leukaemia cells). The trial also demonstrated a good safety profile, with no reports of any severe adverse events.
Unfortunately, the number of the CAR NK cells decreased rapidly 21 days post-infusion, meaning the long-term effectiveness of the treatment must be explored further.
Dr Huang explained that research is planned to look at the use of NK cells from different sources, such as healthy donors. The researchers are also planning to investigate the use of CAR NK cells in combination with other treatments, such as tyrosine kinase inhibitors (TKIs). We are excited to hear of the ongoing research into immunotherapies for AML patients and look forward to seeing further investigations such as this in the future.
Successful trial for high-risk patients
FLT3-ITD gene mutations are commonly observed in AML patients. Dr Erba from the USA presented data from the global quANTUM-First trial, which investigated the use of quizartinib, an inhibitor of the FLT3 protein, in newly diagnosed adult AML patients with the high-risk mutation.
The results of the investigation found that patients who received quizartinib in addition to standard treatment had significantly better outcomes, improving overall survival and duration of remission greatly in comparison to standard treatment alone. The researchers are hopeful that their findings have the potential to change the standard of care for future AML patients. We were pleased to see this session honored during the Presidential Symposium session of the EHA 2022 congress, which is where the best and most groundbreaking research is shared. We hope that this research will improve the lives of many more AML patients going forward.
Policy and public affairs update
We continue to be involved in the National Institute for Health and Care Excellence (NICE) appraisal of oral azacitidine as maintenance treatment for AML. We were glad to be able to put forward a patient to speak at the NICE committee meeting, who told the committee about the impact the potential approval of this treatment would have on patients’ quality of life.
Improvements in CAR T-therapy in paediatrics and young adults
CAR T-cell therapy has demonstrated wonderful success amongst children and young adults with B-cell acute lymphoblastic leukaemia (ALL). CAR T therapy for ALL involves genetically modifying a patient’s own T-cells by adding a lab-made unit called a chimeric antigen receptor (CAR). The CAR improves the cell’s ability to kill cancer cells, which they do by attaching to proteins on the cancer cells. The majority of CAR T-cell products are directed towards an antigen called CD19, which is commonly found on the B cells of patients with B-ALL.
Dr Ghorashian from University College London presented some findings from the CARPALL trial. She explained that patients, who were aged up to 24 years, responded well to CD19-directed CAR T-cell therapy, with a remission rate of 83%. The safety profile of the treatment was excellent, with no reports of serious side effects in any of the patients following their infusions. Despite these initial successes, a proportion of the patients later experienced a CD19-negative relapse. This means that their leukaemia cells had essentially “hidden” from the CAR T-cells by removing the CD19, and the cells now had a different antigen on their surface called CD22.
The incidence of relapse amongst this cohort of patients therefore indicated that there was a requirement for a dual-targeted approach, which means that both CD19 and CD22 could be used as therapeutic targets, killing all the cells before they could switch between the two. This was investigated in the CARPALL AUTO1/22 trial. 11 patients went on to receive this new dual CAR T cell, with 9 patients responding well to the treatment. This trial is still ongoing, but we welcome these improvements and we are hopeful that this trial continues in its success.
Next-generation monitoring in ALL – what is MRD?
Measurable residual disease (MRD) is the amount of leukaemia that can be detected in a sample of bone marrow, and is typically measured using a technique called flow cytometry. This technique involves passing the sample through a machine, the flow cytometer, so that each cell can be identified and counted. The sample is stained before being added to the machine; different fluorescent “tags” attach to different cells. Beams of light then scan each cell, and cells of interest emit a colour. This is then shown as a graph on a computer screen.
However, flow cytometry is not as sensitive as other methods that involve sequencing the genomes of cells; it can miss a cancer cell if very few of them are among many normal cells. Genetic methods can find these small numbers, but can be more expensive.
Dr Orfao of Spain presented data on next-generation flow cytometry techniques, which offer 10x the sensitivity of traditional flow analysis by analysing 10x the amount of cells. This technique took seven years to develop, and uses sophisticated software to assess the results. The results are compared to a database of “normal cells” and the cells are assessed automatically, which makes it much quicker to get the results. This is an exciting development in the use of flow cytometry, making it faster and easier to determine MRD levels for ALL patients, giving patients and their doctors more accurate information about the progress of their leukaemia.
Policy and public affairs update
After some delay, the CAR-T appraisal for adults with ALL in England is taking steps forward now, with the technical engagement expected to take place in August this year and the committee meeting due in October. Leukaemia Care continues to be involved and to advocate for patients in this appraisal.
Why do people change their TKIs and is it the same with every TKI?
This is a real-world study of Canadian registry data. A registry is a collection of data on patients that allows you to explore patterns of actions or outcomes of those patients. Some patterns can only be seen when you look at a large number of patients. Analysing patterns then allows you to understand the impact of decisions that are made by doctors and their patients, such as changing a treatment. A Canadian registry was examined, looking at everyone with chronic myeloid leukaemia (CML) over the age of 18, excluding those who had a transplant as their first treatment, to explore what happened when people changed their TKI treatment.
The researchers looked at two reasons for switching treatments:
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- Intolerance to treatment was defined by a switch due to side effects. The side effects experienced by registry patients were the ones that are commonly known to affect patients on that type of drug, there were no surprising side effects that were unique to the Canadian patient population. This means that the results of the study should be applicable to many patients elsewhere.
- Resistance was defined as the treatment being ineffective.
How did the reason for change depend on the number of treatments you already had? Resistance and intolerance are both fairly common to start with at the first change of TKI, then at the second line of treatment, most people switch (35%) because of intolerance, rather than resistance (5%). At the third, fourth and fifth treatments, both resistance and intolerance become increasingly common reasons to change, but intolerance is also more common.
This is a surprise that intolerance is still a common switch at the fourth or fifth line, where the number of alternatives is getting very small. Subsequently, the decision to switch must be more challenging for the doctor and patient.
So should we be worried about people changing treatment for the CML so often? Does it affect their survival chances?
For the people who do not switch at all, newer treatments (known as second generation TKIs, e.g. dasatinib and nilotinib) offer a slight survival advantage. Those who switch for the first time (second treatment) due to intolerance, have no survival advantage for doing so; on the other hand, you can gain a survival benefit by switching if you are resistant to your first drug.
However, the researcher pointed out that as you come to switching for the 3rd or 4th time, the survival of patients in the Canadian study began to decrease, even if they switched because of intolerance, not resistance. 6.67 times more people switched multiple times due to intolerance than for resistance; i.e. intolerance is a more common reason for switching over all points of a CML pathway. This shows the importance of finding a tolerable drug as soon as possible and the need for more tolerable treatments earlier in the pathway for patients. It’s important to note this was a fairly small study of people in one location and furthe analysis of other causative factors (e.g. whether sex made a difference) is needed, but it provides some guidance for patients and doctors when deciding to change treatment.
Policy and Public affairs updates
In the previous edition of the magazine, we informed readers that we had submitted a response to the National Institute for Health and Care Excellence (NICE) on the appraisal of the TKI drug, asciminib, for treating CML after two or more TKIs.
We are now very pleased to share that NICE have reached a decision to approve asciminib for this group of CML patients. However, whilst we are pleased with this outcome, we would like to see this treatment more widely available for CML patients in the future, such as it being in an option earlier on in a patients’ treatment pathway, without them needing to try as many as two previous drugs beforehand.
Want to find out more about the approval and what this means for you? Read our full announcement here.
Why getting the diagnosis right is so important
Rare types of leukaemia are hard to diagnose. Working out the type of leukaemia can be important for treatment and prognosis, but working out what cells look like, both inside and out, requires many years of study. The more common types of leukaemia have been studied extensively, leading to subtypes like TP53 mutated chronic lymphocytic leukaemia (CLL) or FLT3 positive (AML). Both these subtypes of leukaemia are treated differently to people without the mutations. One researcher outlined why we should do the same for people affected by plasma cell leukaemia (PCL).
Plasma cells are a type of mature blood cell. The most common type of cancer that happens when plasma cells become cancerous is multiple myeloma. However, PCL is a type of plasma cell cancer that is defined by the way cells gather in places outside of the bone marrow. However, sometimes plasma cells escape the bone marrow in people with multiple myeloma too. How do we tell who has myeloma, and who has plasma cell leukaemia? This is important because PCL is a severe illness with a prognosis of around 6 months, whereas myeloma can be highly treatable.
PCL used to be diagnosed by the number of plasma cells found in the blood, if you had more than 20% plasma cells, it was a diagnosis of plasma cell leukaemia (defined in 1974). However, a recent study found that some people with 5% plasma cells in the blood have outcomes that are no better than 20%. This led to the definition of PCL being updated, meaning more patients could be found earlier and the potential for earlier treatment.
Additionally, there are actually also two types of PCL. Primary PCL is where the PCL cells have not come from a multiple myeloma tumor. Secondary PCL is where the cells have transformed from multiple myeloma. But what makes you have PCL instead of MM? PCL do present differently; patients are younger, have hardly any cells in the bone marrow, and have more severe anemia.
But the most important difference is the genetic differences. Genes make proteins, which often represent a protein you can target with treatment or the mutation can change a protein in a way that stops treatment working so well. When patients with different diagnoses were compared, primary PCL were more likely to have one genetic change that happens in a part of DNA that makes BCL2 protein, which can be targeted by treatment. The change was found in 52% of primary PCL patients, never in secondary PCL patients and only 14% of MM patients. This emphasises the importance of knowing what cancer type it is, so it can be treated properly. The presenter showed that those with the genetic change had an increased chance of survival.
This also shows the importance of doing many tests on cells at diagnosis to properly make a diagnosis and the importance of conducting regular research to make sure new things are spotted. For rarer leukaemias, research can be slower to find these genes, as it’s hard to get enough patients together to spot common patterns.
Good news from the MANIFEST study for myelofibrosis
The MANIFEST study was presented by Professor Claire Harrison of Guys and St Thomas’ hospital in London. The study looked at a new drug called pelabresib combined with ruxolitinib for myelofibrosis (MF) patients. More treatments are badly needed for those who are resistant to or cannot tolerate JAK inhibitors, the most common existing treatment. Pelabresib is a BET inhibitor. BET is a protein that is part of a pathway in the cells that causes MF and JAK is another protein in the same pathway. This study is showing if BET and JAK inhibitors work better together, although results are only up to week 24 of the trial so far.
There were two groups presented; data about people who are newly diagnosed, and people who have already tried JAK inhibitors. Across both groups, most patients were mainly high risk patients due to being anemic and their spleens were large. They also had high risk genetics. These things mean that these patients may not respond well to treatment.
However, Professor Harrison presented information showing that patients improved in a number of different ways. Most patients did see a decrease in their spleen size. Of the newly diagnosed patients, 80% got a 35% reduction or more in spleen size and the average spleen reduction was 50%. For previously treated patients, 30% of people got a spleen reduction of 35% or more, with an average reduction in spleen size of 18%. Spleen size decreasing is really important, as an enlarged spleen can be very uncomfortable for patients.
There was also evidence that the symptoms experienced by patients decreased. On average, newly diagnosed patients had a 60% lower score in the questionnaire about how they rate their symptoms (TSS score). The average TSS score reduction of those who had been previously treated was 47%. Importantly, people also stayed on their treatment, meaning these responses continued to improve over the time up to the data collection cut off for this presentation. This shows side effects were tolerable for the patients.
As well as spleen reduction, Professor Harrison listed a number of other improvements thanks to the treatment. This included improvements in the amount of scarring in the bone marrow, which is scored or graded by appearance under the microscope. 40% of the newly diagnosed patients and 39% of previously treated had at least one grade improvement at some point. Many of these patients also had the improvement stay until their next bone marrow examination, showing the response to be durable.
Prof Harrison stated that the study has shown so far that there is improvement clinically for these patients, despite being only week 24 of the study. There is another study open for this treatment in newly diagnosed patients, plus lots of other treatments that are very similar, so there is hope for MF treatment in the future.
Policy and public affairs updates
Back in May this year we were disappointed to learn that ropeginterferon alfa-2b (Besremi) for polycythaemia vera (PV) patients has been rejected for use on the NHS in Scotland, as patients with PV have few other options. The treatment is not available elsewhere in the UK, and there are no plans at present to appraise the drug for use elsewhere. The Scottish Medicine Consortium (SMC) committee felt that, even though The Patient Access to Cancer Care Excellence (PACE) meeting statement highlighted strong support from patients and clinicians for another treatment option, there was not enough evidence from the clinical trials for the committee to be confident the treatment would be effective.
Up until the launch of Spot Leukaemia we continued to work on the #WatchWaitWorry campaign and met with parliamentarians across the nation as well as cancer alliances. We then turned attention to the policy planning for Spot Leukaemia in collaboration with Leukaemia UK.
Ella, our Policy and Public Affairs Officer, attended a meeting hosted by the All Party Parliamentary Group on Cancer (APPGC) in the houses of parliament in July. This meant they got to discuss the 10 year cancer plan before it was published and make sure the views and experiences of leukaemia patients were represented to MPs.
Ella also met with the NHS England vaccination team and the vaccines Minister, Maggie Throup MP, to talk about issues patients have told us they have faced accessing COVID-19 vaccines. Leukaemia Care plan to work with the NHS for future vaccine campaigns to try to clear up any uncertainties, simplify the communications and ensure that everyone who needs it has access. This meeting also gave patient groups another chance to push the Minister for further transparency into the timelines and process of reviewing the procurement of Evusheld.