Long term follow up of NI-0501 in HLH patients
Research type
Research Study
Full title
A multicentre study for the long-term follow-up of HLH patients who received treatment with NI-0501, an anti-interferon gamma monoclonal antibody
IRAS ID
207694
Contact name
Anupama Rao
Contact email
Sponsor organisation
NovImmune SA
Eudract number
2012-005753-23
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
111015, US IND
Duration of Study in the UK
2 years, 6 months, days
Research summary
Summary of Research
Haemophagocytic lymphohistiocytosis (HLH) results from a defective immune system and is often characterised by a severe inflammation that the body cannot switch off. The overstimulated immune system produces an excessive number of certain immune cells which accumulate in tissues and organs causing damage and also attacking healthy blood cells, consuming and killing them. HLH can be inherited (primary HLH) which is extremely rare and is normally seen in early childhood; or acquired (secondary HLH) which can occur at any age. Currently, there is no specific treatment approved for HLH. Primary HLH is managed by giving a combination of medications that can control the disease and help patients achieve the stable condition required for stem cell transplantation, which may potentially cure HLH. Once stable condition is achieved, a mixture of medications is given to suppress the immune system before transplantation. Transplantation replaces the ill functioning immune system with cells that can develop into healthy blood cells and a healthy immune system.This study will monitor the long-term safety profile of participants who have received NI-0501. Participants of both sexes will be eligible to enrol if they have received at least one dose of NI-0501 in the previous study NI-0501-04. The same regimen (i.e. NI-0501 with dexamethasone), dose and frequency of administration as used in the 8th week of NI-0501 treatment in the previous study participated in will be carried forward in this study, providing that the treatment is well tolerated and the disease is not progressing. If a participant receives transplant during the course of the previous study, they will enter the NI-0501-05 study as per the relevant post-transplant visit treatment schedule.
Summary of Results
What was the study about?
Long-term outcome of patients with HLH (haemophagocytic lymphohistiocytosis) who have received emapalumab.What is Haemophagocytic lymphohistiocytosis?
HLH stands for haemophagocytic lymphohistiocytosis. HLH is a rare and serious illness that usually occurs in infants and young children, but it can also occur in adults. There are two types of HLH:
• Primary/familial: in which the disease is inherited, meaning that it is passed down from parents to their children and so runs in families. People with this type of HLH are born with the illness.
• Secondary: in which the illness is not normally inherited, meaning that people can develop the illness at any point during their lifetime. This type of HLH is usually caused by other, non-inherited reasons, such as infections or other underlying diseases.
HLH is an illness where certain white blood cells, called histiocytes and lymphocytes, become overactive and attack other blood cells in the body, causing damage to the body’s own tissues and organs.
Many people with HLH have higher than normal levels of a protein called interferon gamma (IFNγ). IFNγ is important for the body’s response against fungal, bacterial, and viral infections. However, too much IFNγ can trigger the body’s defense system – the immune system – to attack the body’s own healthy tissues and organs. Some symptoms of HLH are fever, yellow coloured skin and eyes, rash, and enlarged liver, spleen, and other body organs. When secondary HLH occurs in people with a rheumatology disease, the HLH is also called macrophage activation syndrome (MAS), a form of increased activation and spreading of specific white blood cells in the body.What medicine did the participants take?
Emapalumab, or NI-0501, is a type of human antibody (a protein that supports the body to fight diseases) that can help control the amount of IFNγ in the body. During the study, some participants received emapalumab, but not all of them. Some participants were only monitored during the course of this study after having previously received emapalumab either in another study or under compassionate use. Compassionate use is a special situation when a patient with a serious illness can receive treatment with an experimental medicine when there are no other approved treatments available and if the participant could not enter a clinical trial.Why was this study done?
The main questions the study doctors wanted to answer in this study were:
• How many participants experienced at least one side effect during the 1-year follow-up after their last emapalumab treatment or after receiving haematopoietic stem cell transplantation (HSCT; bone marrow transplant)?
• How many participants had serious side effects after taking emapalumab?
• What serious side effects did participants have during the study?
• How many participants had serious side effects related to emapalumab?
• How many participants had non-serious side effects related to emapalumab?
• How many participants stopped study treatment because of side effects?
The other questions the study doctors wanted to answer in this study were:
• How did the participants’ HLH behave during the year after taking emapalumab?
• What was the participants survival outcome, at last study visit?
• How many participants achieved engraftment (when the blood-forming cells received during their transplant started to grow and make healthy blood cells)?
• How many participants achieved donor chimerism (when more than 95% of the donor blood cells are ‘accepted’ in the host [recipient] body)?
• How many participants had graft-versus-host disease (when donated bone marrow cells view the host body as foreign, and the donated cells start attacking the host’s organs)?
• What was the macrophage activation syndrome (MAS) activity level of participants?
• How much emapalumab was present in the blood of participants during the course of this study?
• How much IFNγ was present in the blood of participants during the course of this study?
The answers to these questions are important to increase the knowledge of emapalumab treatment in patients who have HLH. This summary gives the results to the main questions the study doctors wanted to answer.Who took part in this study?
This study included 58 participants with HLH who had received at least one dose of emapalumab in either (i) a previous study (‘parent’ study), or (ii) through ‘compassionate use’, in which no long-term follow-up after treatment was available.
• A total of 33 females participated
• A total of 25 males participated
• Almost all (57 out of 58) participants were less than 19 years of age • A total of 37 participants had primary/familial HLH and received emapalumab in another study • A total of 14 participants had secondary HLH and received emapalumab in another study • A total of 7 participants with either primary/familial or secondary HLH had received emapalumab through compassionate use • Participants came from the following countries: France, Italy, Spain, United Kingdom, and United States.What happened during the study?
This study was a long-term follow-up study. This means that the study doctors continued to follow the participants for a long period of time, up to 1 year.
Participants were enrolled in this study after having received emapalumab in other HLH studies (parent study) or as part of compassionate use treatment. Some participants continued to receive emapalumab treatment for their HLH during parts of this study. They either received emapalumab at the same dose and frequency (from their previous study participation or compassionate use), or they received a different dose or frequency (as needed, to control their HLH).
During the course of this study, some participants received a type of bone marrow transplant called a haematopoietic stem cell transplantation (HSCT). Bone marrow is a type of tissue found inside the bones and is responsible for making all the different types of blood cells that our body needs. In primary/familial HLH, a bone marrow transplant replaces the bone marrow with healthy cells. This type of procedure is the only possible cure for primary/familial HLH. Treatment with emapalumab before the transplantation procedure might help a patient with HLH to achieve a stable condition that is required prior to performing a transplant.
In this study, participants attended follow-up visits for up to 1 year after the last dose of emapalumab or after their bone marrow transplant was performed.
Participants were divided into three groups based on the parent study/compassionate use:
• Group 1: Included 37 participants with primary/familial HLH who completed the NI 0501 04 parent study • Group 2: Included 14 participants with secondary HLH who completed the NI-0501-06 parent study. No participants in this group received emapalumab during the long-term follow-up study.
• Group 3: Included 7 participants with either primary/familial or secondary HLH who had received emapalumab under compassionate use.
The number of participants who completed the study was:
• 24 out of 37 participants in Group 1
• 13 out of 14 participants in Group 2
• 4 out of 7 participants in Group 3What were the results of the study?
The data shown in this summary are the average results from the study; individual participant results could differ from the average results. To learn more about this study and the other questions the study doctors asked, visit the websites listed at the end of this summary.
Main Questions of the Study:
Side effects:
Side effects are unwanted medical problems (such as rash) that can happen during or after treatment. Side effects could have been caused by emapalumab, by another drug the participant was taking, or by other/current diseases that the patient may have. Sometimes the cause of side effects is not known. Study doctors often compare side effects from many studies to understand the side effects of a new medicine.
How many participants experienced at least one side effect during the 1-year follow-up after their last emapalumab treatment or after receiving HSCT?
To answer this question, study doctors observed the participants for any side effects that may have occurred during the study. Participants could report these side effects during the scheduled visits with their study doctors or at any time during the study via a phone call.
The number of study participants who experienced/reported at least one side effect during the study were:
• Group 1: all 37 participants (100%)
• Group 2: 12 of the 14 participants (86%)
• Group 3: all 7 participants (100%)
The most common side effects reported during the study were:
• Fever (37 occurences in 21 participants)
• Vomiting (19 occurences in 11 participants)
• Re-activation or flare of the participant’s underlying HLH (18 occurences in 12 participants)
None of these side effects were assessed by the treating study doctors as having been caused by emapalumab.Serious side effects:
Side effects are considered “serious” if they are life-threatening or cause death, lasting problems, or result in the participant needing hospital care. In some studies, participants need to stop study treatment because of side effects.
The websites listed at the end of this summary have detailed information about all the side effects that were reported in this study.
How many participants had serious side effects after taking emapalumab?
The number of participants with serious side effects in the study was:
• 28 out of 37 participants in Group 1
• 3 out of 14 participants in Group 2
• 6 out of 7 participants in Group 3
What serious side effects did participants have during the study?
The most common serious side effects reported during the study were:
• Re-activation or flare of the participant’s underlying HLH (10 occurrences in 8 participants)
• Fever (8 occurrences in 6 participants)
• Septic shock (6 occurrences in 5 participants).
None of these serious side effects were assessed by the treating study doctors as having been caused by emapalumab.
Emapalumab-related side effects:
How many participants had serious side effects related to emapalumab?
During this study, only 1 participant in Group 1 had a serious side effect (anaemia) that the treating study doctor thought could be related to emapalumab.
How many participants had non-serious side effects related to emapalumab?
During this study, 4 out of 37 participants in Group 1 (10.8%) had non-serious side effects that the treating study doctor thought could be related to emapalumab. The side effects thought to be related in Group 1 included:
• Rash
• Infections
• Decreases in the number of blood cells
• Increases in heart rate
• Anaemia (hemolytic)
Only 1 participant in Group 2 had a non-serious side effect (lung infection) that the treating study doctor thought could be related to emapalumab.
No participants in Group 3 had a non-serious side effect that the treating study doctor thought could be related to emapalumab.
How many participants stopped study treatment because of side effects?
No participants in any of the three groups stopped study treatment because of a side effect.How did the participants’ HLH behave during the year after taking emapalumab?
To answer this question, the study doctors counted the number of days between the time when a participant’s HLH was fully controlled and the time when the HLH was no longer fully controlled, or when a participant died. In addition, the study doctors assessed the participants throughout the study.
For Group 1, the time that participants were living with their HLH controlled was calculated using specific criteria. This was done for 37 participants and the median amount of time was 58 days. The median is the middle number in a sequence of numbers. The study doctors also did an assessment and, of the 26 participants who were assessed at the 1-year visit, one participant was reported as having maintained a partial HLH control and 25 participants were reported as having maintained full HLH control, i.e., complete response.
For Group 2, the median time that a first control of HLH lasted, when using specific criteria, was calculated for 13 participants. The median amount of time the participants were living with their HLH fully controlled for the first time was 61 days. When the study doctors evaluated the outcome, 13 of the 14 patients had maintained full HLH control, i.e., complete remission until the last study visit.
What was the participants survival outcome, at last study visit?
• Group 1: 28 of the 37 participants were alive at the last study visit.
• Group 2: All 14 participants were alive at the last study visit.
• Group 3: All participants were alive at the last study visit.
How many participants in Group 1 achieved engraftment?
Engraftment in bone marrow transplantation is when the body accepts the transplanted cells, and they start growing to make healthy blood cells.
In this study, study doctors looked at how many participants achieved engraftment.
Of the 37 participants in Group 1, 29 participants underwent transplantation. Of these 29 participants, six participants (approximately 20.7%) did not achieve a successful engraftment.
How many participants in Group 1 achieved donor chimerism?
Donor chimerism was achieved when more than 95% of the donor blood cells were ‘accepted’ in the host body (recipient). To answer this question, study doctors took regular blood samples during the study to look at how many donor cells were present compared to the recipient’s own blood cells.
During the study, 21 out of 29 participants who had a transplant in Group 1 (approximately 72.4%) achieved donor chimerism.
How many participants in Group 1 had graft-versus-host disease?
Graft-versus-host disease is where the donated bone marrow cells view the host (recipient) body as foreign, and the donated cells attack some of the organs. To answer this question, study doctors looked at participant symptoms (such as rash, diarrhea, nausea, vomiting, abdominal cramping, yellow discoloration of the skin and/or eyes) and other signs (fever, abnormal blood test results).
During the study, 7 out of 29 participants in Group 1 (approximately 24.1%) had graft-versus-host disease.
What was the MAS activity level of participants in Group 2?
The study doctors wanted to evaluate the MAS activity level during the 1-year follow-up period. To answer this question, the study doctors measured the MAS activity on a scale of 0 to 10. The higher the number, the more severe the MAS activity. Study doctors measured the activity at three different times during the study: at the start of the study (baseline), on Day 100, and at the end of the study (Year 1).
No MAS activity was observed in Group 2 participants at start of the long-term follow-up study and Day 100 (score was 0). At the end of the study (Year 1), the average MAS activity score for 13 participants in Group 2 was 0.2.
How much emapalumab was present in the blood of participants during the course of this study?
To answer this question, the study doctors took blood samples from all participants from the start of the study and until the drug was no longer measurable to measure how much emapalumab was present in the blood and for how long.
The average amounts of emapalumab in the blood (in micrograms per litre) for participants in Group 1 at different time points are listed below. The participants had a different number of infusions, doses and frequency of doses, making it difficult to draw a conclusion on the emapalumab amount in this group of participants. However, the amount of emapalumab in the blood decreased over time as expected.
• Infusion Day 1 (22 participants): 165148.4 micrograms per litre
• 100 days after transplant (21 participants): 4138.0 micrograms per litre
• 6 months after transplant (19 participants): 730.6 micrograms per litre
• One year after transplant (12 participants): 80.5 micrograms per litre.
The average amounts of emapalumab in the blood (in micrograms per litre) for participants in Group 2 at different time points are listed below. The amount of emapalumab decreased over time, but in average decreased a bit slower compared to what was observed in Group 1.
• Day 1 (12 participants): 20968.0 micrograms per litre
• Day 100 (10 participants): 8515.3 micrograms per litre
• Month 6 (8 participants): 1628.5 micrograms per litre.How much IFNγ was present in the blood of participants during the course of this study?
To answer this question, the study doctors took blood samples from all participants throughout the study to measure the total amount of IFNγ in the blood.
For Group 1, the average IFNγ concentration decreased from 5290.4 nanograms per litre (ng/L) at the Infusion Day 1 visit to 447.4 ng/L by the 1-year study visit.
For Group 2, the average IFNγ concentration decreased from 5544.3 ng/L at the first study visit (baseline) to 1111.0 ng/L by the 1-year study visit.How was this study useful for participants and study doctors?
This study helped study doctors learn more about the long-term safety of emapalumab treatment in patients with HLH. Study doctors look at the results of many studies to decide which treatments work best and are safest. Other studies may provide new information or different findings. Please talk to a doctor before changing any treatment you are taking or if you have any questions about these study results.REC name
West Midlands - Coventry & Warwickshire Research Ethics Committee
REC reference
16/WM/0366
Date of REC Opinion
17 Oct 2016
REC opinion
Further Information Favourable Opinion