CML real-world analysis finds increased second malignancies and comorbidities compared to clinical trials

7th July 2022

Chronic myeloid leukaemia real-world data reveals a higher incidence of second cancers and cardiovascular disease than seen in trials

Real-world registry data on patients with chronic myeloid leukaemia (CML) have revealed a higher incidence of second malignancies and cardiovascular disease among patients than was observed in the original clinical trials. These were the key findings from an analysis by a collaborative group from Spain and the US.

Chronic myeloid leukaemia is a cancer that develops from myeloid blood stem cells. In an analysis of data from 2017, it was estimated that globally, there were an estimated 34,179 incident cases of CML recorded and 24,054 CML-related deaths.

CML is characterised by the presence of the Philadelphia chromosome, which represents the product of a reciprocal translocation between chromosomes 9 and 22 leading to the formation of BCR-ABL1, a tyrosine kinase and which is also a potent oncogene. 

In 2001, Imatinib an orally administered tyrosine inhibitor was introduced after data showing that the drug was capable of blocking proliferation and inducing apoptosis in CML cell lines.

Imatinib was the first tyrosine kinase inhibitor (TKI) approved for the management of chronic myeloid leukaemia and found to provide an acceptable response in approximately 60% of patients. In fact, after a median follow-up was 10.9 years, patients treated with imatinib had an estimated overall survival rate of 83.3%.

While TKI drugs have significantly improved the treatment for patients with CML, there is limited supportive real-world data on these drugs. As a result, for the present study, researchers sought to better understand not just whether in practice, these drugs improved the survival of patients, but if there were any emergent adverse effects from TKI therapy.

They undertook an analysis of registry data via the TriNetX platform which provided information on CML patients derived from a total of four different cohorts; H120; EMEA Collaborative Network; the US Collaborative Network and the Global Collaborative network.

For each of the four cohorts, the researchers identified a propensity-matched control cohort, i.e., non-CML patients, matched for age and gender. For the analysis, the researchers focused on the development of other malignancies, cardiovascular disease, infections and finally survival.

CML treatment-related outcomes

Using the TriNetX platform enabled the identification of 6133 patients from the four databases. The most commonly prescribed TKI was imatinib followed by dasatinib although other agents used included nilotinib, bosutinib and ponatinib.

When looking at the development of a second malignancy, the H120 had a non-significantly higher incidence compared to the control group (43.9% vs 28.1%, p = 0.079). However, the risk of developing a second malignancy was significantly higher in both the EMEA (odds ratio, OR = 2.61, 95% CI 1.75 – 3.89) and in the US cohort (OR = 8.72, 95% CI 7.96 – 9.55).

In both the EMEA and the US cohort, there was also a statistically higher incidence of cardiovascular disease (EMEA: OR = 1.68, US cohort: OR = 1.88) compared to controls. Moreover, this difference was also significant for each of the different drugs within the TKI class. Fortunately, there were no significant differences between the cohort in relation to infectious diseases.

Finally, there did not appear to be a difference in survival between the CML and non-CML cohorts in any of the four databases.

The authors concluded that while there were similar mortality benefits to the general population among those with CML treated with TKIs, what was of greater concern was the development of both second malignancies and cardiovascular disease.

Citation
Sanz A et al. Outcomes and patterns of treatment in chronic myeloid leukemia, a global perspective based on a real-world data global network Blood Cancer J 2022

Paxlovid remains effective in those vaccinated against COVID-19

4th July 2022

Israeli researchers have found that paxlovid use in those at risk of COVID-19 progression remains effective even in fully vaccinated patients

The effectiveness of the anti-viral drug paxlovid in preventing the progression of COVID-19 remains even in those who have been adequately vaccinated against the virus according to the results of a real-world study by Israeli researchers.

Paxlovid consists of nirmatrelivir, a protease inhibitor against COVID-19 and ritonavir, which reduces the in vivo metabolism of nirmatrelivir. The published data for the drug (the EPIC-HR trial) suggested that treatment of symptomatic COVID-19 in patients at risk of progression to severe disease, results in an 89% lower risk compared to placebo.

Nevertheless, the study was undertaken before omicron became the main circulating variant and therefore the generalisability of the study’s findings are potentially limited.

Consequently, for the present study, the Israeli team decided to undertake a large, retrospective cohort study of high-risk COVID-19 patients, to assess the effectiveness of paxlovid at preventing progression to severe COVID-19 and subsequent death during the time when omicron was the predominant strain.

Using a large, national health service database, the researchers identified all adults (18 years and over) who tested positive for COVID-19 but restricted the search to those who would be suitable candidates for treatment with paxlovid, i.e., those who were older than 60 years, with a body mass index (BMI) greater than 30 and with co-morbidities including diabetes, hypertension and cardiovascular disease.

However, unlike in the EPIC-HR trial, where those who had been vaccinated were excluded, for the present analysis, researchers included patients, regardless of their vaccination status.

The main outcome of the study was a composite of severe COVID-19 or COVID-19-related mortality. For their analysis, the researchers included demographic and co-morbidity data and which were adjusted for in the analysis.

Paxlovid and progression of COVID-19

A total of 4,737 individuals with a mean age of 68.5 years (42.1% male) were treated with paxlovid and compared with 175,614 individuals who tested positive but who did not receive the drug. In total, 77.8% of those given paxlovid had adequate COVID-19 vaccination compared to 75% of those in the non-paxlovid group.

Overall, the primary outcome occurred in 39 individuals receiving paxlovid compared to 903 in those not given the drug. Paxlovid was therefore associated with a significantly lower risk of severe COVID-19 or mortality (hazard ratio, HR = 0.54, 95% CI 0.39 – 0.75). Moreover, among the whole cohort, having adequate COVID-19 vaccination, was also associated with a significantly lower risk of the primary outcome (HR = 0.20, 95% CI 0.17 – 0.22).

When the analysis was restricted to those diagnosed with COVID-19 when omicron was the main circulating variant, paxlovid was also associated with a greater reduction in the primary endpoint (HR = 0.43, 95% CI 0.64 – 0.85).

Interestingly, among those given paxlovid and who were adequately vaccinated, there was still a significant reduction in the primary outcome (HR = 0.62, 95% CI 0.39 – 0.98) as well as among those not vaccinated (HR = 0.52, 95% CI 0.32 – 0.82).

The authors concluded that their study had demonstrated that in a real-world setting and during the period of time when omicron was the dominant variant, paxlovid was associated with a significant reduction in progression of COVID-19 and COVID-19-related mortality.

Citation
Najjar-Debbiny R et al. Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients Clin Infect Dis 2022

Real-world analysis reveals high level of recurrent cardiovascular events and death 6 months after primary episode

28th March 2022

Recurrent cardiovascular events and death occur largely within 6 months of the primary event according to an analysis of real-world data

Both recurrent cardiovascular events (CVs) and death have been found to occur mainly within the first 6 months after the primary event according to a real-world analysis of registry data by researchers from the Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.

Cardiovascular disease (CVD) is the leading cause of deaths and disability worldwide and the World Health Organization estimates that CVD is response for 17.9 million lives lost each year.

Despite falls in the mortality rates of CVD across Europe, more than 4 million people continue to die each year from the disease, with more than 1.4 million dying prematurely, before the age of 75 years.

Moreover, recurrent cardiovascular events are not uncommon and one study among patients with acute coronary syndrome (ACS) found that 9% of patients experienced a recurrent cardiovascular event in the post-ACS setting during a median follow-up of 1 year.

But which factors are associated with an increased risk of recurrent CVs and death among secondary prevention patients, and when are these most likely to occur, was the subject of the present, registry-based study by the Finnish team.

They undertook a retrospective analysis, using hospital data, of adult patients who experienced their first atherosclerotic cardiovascular disease (ACVD) event between 2012 and 2016. The team defined an ACVD event as a myocardial infraction (MI), unstable angina (UA), ischaemic stroke (IS) or a transient ischaemic attack (TIA).

In addition, a recurrent event as a new diagnosis of the same condition as the index event, a minimum of 7 days from the first episode and all mortality data were retrieved from the hospital database.

Characteristics of cardiovascular events

In total, 48,405 adults with a median age of 71.5 years (53.8% male) were followed for a mean of 2.2 years. Among the whole cohort, 40.1% had an IS, 29.4% and MI and 19.5% a TIA as their index event. Co-morbidities included hypertension (12.9%) and diabetes (16.7%).

Among the current CVs, death was the most common subsequent event (61.5%) and a recurrent event occurred in 38.5% of patients. It was also clear that the category of subsequent events mirrored the initial episode (i.e., a second MI after the first).

The cardiovascular events rate also increased after each recurrence. For instance, the combined recurrent/deaths events rate increased from 13.4 per 100 patient-years for the first event, to 36.8 for the third recurrent event.

In terms of the time to the recurrent event, after 6 months, 14% of patients had suffered any recurrent event or had died. This stabilised over time, so that after 5 years, 41.5% of patients had either suffered an event or died.

When considering the risk factors most significantly associated with risk of subsequent cardiovascular events, this increased with each increased year of age (hazard ratio, HR = 1.02 (95% CI 1.02 – 1.02, p < 0.001). Other significant factors included the presence of diabetes (HR = 1.21, 95% CI 1.11 – 1.32, p < 0.001) and hypertension (HR = 1.18).

The risk of death was also significantly associated with male gender (HR = 1.18) but the only co-morbidity was diabetes (HR = 1.63, 95% CI 1.53 – 1.73, p < 0.001). Moreover, male gender and diabetes were also significantly associated with the risk of recurrency to death.

The authors concluded that given their findings, an acute CV event should be promptly followed by secondary prevention measures.

Citation
Toppila I et al. Cardiovascular event rate and death in high‐risk secondary prevention patient cohort in Finland: A registry study Clin Cardiol 2022

Comirnaty COVID-19 booster shows greater than 90% effectiveness in over 50s

6th December 2021

A Comirnaty booster dose given to those aged 50 years and over provides >90% vaccine effectiveness against COVID-19 infection

A Comirnaty booster dose in those over the age of 50 provides a greater than 90% vaccine effectiveness, irrespective of whether individuals had been previously fully vaccinated with ChAdOx1-S (AstraZeneca) or Comirnaty (BNT162b). This was the finding of a study by a team from the UK Health Security Agency, UK, which is available online but not published in a peer-reviewed journal.

With evidence that the efficacy of COVID-19 vaccines wanes 20 weeks after vaccination, the Joint Committee on Vaccination and Immunisation (JCVI) in the UK issued a statement highlighting the need for a booster dose of COVID-19 vaccines in an effort to combat the virus during the winter months. Moreover, after a review of the available data on booster responses, the JCVI advised a preference for the Comirnaty vaccine as the booster dose irrespective of which product was used to provide the initial full vaccination.

In the present study, the UK team sought to estimate the real-world effectiveness of a single Comirnaty booster dose in those aged 50 years and older. The researchers compared vaccination status in this patient cohort, who were symptomatic for COVID-19 and with a positive PCR test result. Data was obtained from the National Immunisation Management System (NIMS) and a booster dose was defined as one given 140 days or more after a second vaccination dose. Vaccine effectiveness was adjusted in regression models for age, deprivation, ethnicity, care home residence status and co-morbidities. The analysis was also stratified by the primary vaccination received, i.e., either ChAdOx1-S (AstraZeneca) or Comirnaty and vaccine effectiveness assessed at several time points e.g., 2 to 6 days post booster dose and 14 or more days later.

For the primary analysis, the team compared vaccine effectiveness in those who received a booster with those who had been fully vaccinated but without a booster dose. In a secondary analysis, they determined the absolute vaccine effectiveness which was the difference in rates of infection between those who had two doses (at least 140 days apart) and a booster with those who were unvaccinated.

Findings

There were 271,747 eligible tests in people 50 years and older, of which 13,568 (5%) were unvaccinated with the remainder being fully vaccinated with either ChAdOx1-S or comirnaty (BNT162b)

The vaccine effectiveness from a BNT162b booster in those who were fully vaccinated with ChAdOx1-S was 87.4% (95% CI 84.9 – 89.4) and 84.4% (95% CI 82.8 – 85.8%) in those fully vaccinated with BNT162b.

In the secondary analysis, compared with unvaccinated individuals, those fully vaccinated with a primary course of ChAdOx1-S had an absolute vaccine effectiveness of 93.1% (95% CI 91.7 – 94.3%) and 94% (95% CI 93.4 – 94.6%) in those fully vaccinated with BNT162b.

Interestingly, when compared with those who were fully vaccinated but had not received a booster dose, the vaccine effectiveness after 20 or more weeks was 44.1% for the ChAdOx1-S vaccine and 62.5% for BNT162b.

In their conclusion, the authors wrote ‘our study provides real world evidence of significant increased protection from the booster dose against symptomatic disease in those aged over 50 years of age irrespective of which primary course was received.’

Citation

Andrews N et al. Effectiveness of BNT162b2 (Comirnaty, PfizerBioNTech) COVID-19 booster vaccine against
COVID-19 related symptoms in England: test negative case-control study.

Allergen immunotherapy effectiveness confirmed in long-term real-world study

3rd December 2021

Allergen immunotherapy in patients with allergic rhinitis and/or asthma was effective over a 9-year period in a real-world study

The effectiveness of allergen immunotherapy (AIT) in allergic rhinitis (AR) patients both with and without asthma has been confirmed in a 9-year retrospective analysis by researchers from the Paediatric Pulmonology and Allergy, Children’s Doctor Service, Heidelberg, Germany.

Allergies represent an abnormal immune system reaction to otherwise harmless allergens and in the UK, AR is estimated to affect 10-15% of children and 26% of adults. In addition, patients with AR can also suffer with asthma as a co-morbidity, with studies suggesting that 10% to 40% of AR patients have asthma. Furthermore, the presence of AR is associated with an incremental adverse impact on the disease-specific quality of life in patients with asthma and the level of asthma control.

Allergen immunotherapy (or desensitisation treatment) involves exposure to increasing doses of an allergen such as grass pollen, dust mite, or cat dander. AIT can be given via the subcutaneous or sublingual route, both of which have been shown to be effective treatment for patients with AR. Nevertheless, there is a recognised lack of information from studies on the effectiveness of AIT in real-world studies and over the longer term.

In order to address this gap in the evidence, the German researchers undertook the Real World effectiveness in allergy immunotherapy (REACT) study, primarily to assess the efficacy of AIT over a period of years. Using a retrospective, observational, propensity score matched cohort study, the team analysed health insurance claims from 2007 to 2017 and included AR patients with and without asthma and who had received an AIT prescription. These individuals were then propensity-score matched with AR individuals (also with or without asthma) but who had not been prescribed AIT. The primary outcome of the study was set as AR prescriptions in each follow-up year and secondary outcomes included asthma prescriptions, severe asthma exacerbations and any changes in the individual’s asthma treatment steps.

Findings

Between 2007 and 2017, 115,098 individuals had at least one AIT prescription, of whom, 46,024 with a mean age of 29.5 years (53% male) were propensity score matched. In addition, 14,614 AR patients with AR and co-existing asthma (mean age, 28.3 years, 54% male) were also matched with controls. However, over the 9 years, the study population declined, leaving 3692 individuals in the main cohort and 1142 with co-existent asthma.

When compared to control patients, AIT use was consistently associated with greater reductions in both AR and asthma prescriptions. In addition, there was a significantly greater likelihood that patients using AIT would have an asthma treatment step-down (p < 0.0001) and a reduction in severe asthma exacerbations (p < 0.05).

The authors concluded that their study had confirmed the real-world effectiveness of AIT as evidenced by sustained reductions in AR and asthma prescriptions, prevention of asthma exacerbations, and improved and sustained long-term asthma control.

Citation

Fritzching B et al. Long-term real-world effectiveness of allergy immunotherapy in patients with allergic rhinitis and asthma: Results from the REACT study, a retrospective cohort study. Lancet Regional Health Europe 2021

Atezolizumab and nivolumab prolong overall survival compared with docetaxel in NSCLC

19th November 2021

Atezolizumab and nivolumab both produce similar, higher improvements in overall survival compared to docetaxel in NSCLC patients

Atezolizumab and nivolumab have been found to prolong overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) cancer say researchers from Hoffmann-La Roche, Basel, Switzerland. NSCLC accounts for 85% of all lung cancers although nearly 40% of patients are diagnosed at stage 4, which has a poor prognosis, warranting systemic therapy. Treatment of NSCLC can be achieved with platinum-based chemotherapy although many patients relapse and in such cases, mono-therapy with the chemotherapeutic agent, docetaxel, has been found to be effective.

In recent years it has been discovered that developing tumours are capable of evading the immune system by avoiding checkpoint signals designed to prevent uncontrolled activation of T lymphocytes. Monoclonal antibodies including nivolumab and atezolizumab, work to either inhibit checkpoint PD-1 surface receptors (nivolumab) or its ligand, PD-L1 (atezolizumab) thereby blocking these receptors and signals, enabling the immune system to combat the tumour. Although both monoclonal antibodies are approved for use in NSCLC, there is a lack of head-to-head studies comparing these two agents even in comparison to docetaxel.

For the present study, researchers examined real-world studies contained within the US nationwide electronic health record, in which patients with advanced NSCLC and prior platinum-based therapy, who had been started on either atezolizumab, nivolumab or docetaxel. They included adults (18 years and over) diagnosed with locally advanced and/or metastatic NSCLC, none of whom had been previously treated with one of the three agents. The team also only included patients with at least 6 months of follow-up data and set the primary endpoint as overall survival.

Findings

In total, 3336 patients were included in the analysis with 206 receiving atezolizumab, 500 docetaxel and 2630 nivolumab. Patients in the atezolizumab and nivolumab groups were of a similar mean age, 68.3 and 67.3 years respectively while those in the docetaxel group were slightly younger with a mean age of 65.6 years.

Compared to docetaxel, use of atezolizumab was associated with a significantly longer survival (adjusted hazard ratio, aHR = 0.79, 95% CI 0.64 – 0.97, p = 0.02) even among those with different cancer stages. In contrast, the adjusted hazard ratio for atezolizumab compared with nivolumab was 1.07 (95% CI 0.89 – 1.28, p = 0.47) and this did not differ between patients at different cancer stages. However, the authors recognised that their analysis may not have been sufficiently powered to detect a difference between these two treatments.

The authors concluded that their real-world data suggested that atezolizumab and nivolumab produced a longer overall survival than docetaxel among those who had failed to respond to platinum-based chemotherapy.

Citation

Ramagopalan S et al. Comparative Effectiveness of Atezolizumab, Nivolumab, and Docetaxel in Patients With Previously Treated Non–Small Cell Lung Cancer. JAMA Netw Open 2021

Real-world data show that biologics for psoriasis are less effective in practice

7th December 2020

Randomised controlled trials (RCTs) define the expected efficacy of a drug. However, real-world studies serve to demonstrate the effectiveness in clinical practice, which might be very different.

Real-world data can be derived from patient registries and are of value because they illustrate whether the expected efficacy determined in a randomised trial holds up in practice. Using information held in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a team from the Centre for Dermatology, Salford, UK, examined the comparative effectiveness of two biologics, secukinumab and ustekinumab used in patients with moderate to severe psoriasis, defined in terms of a psoriasis and area severity index (PASI) of 12 or more prior to starting with either biologic. The PASI serves as a measure of disease severity with scores above 10, indicating at least moderate disease severity. The researchers restricted the drug initiation dates to on or after September 2013 (when both drugs became available) and before September 2018, to allow for patients to have completed at least 12 months of therapy. The primary outcome for the study was the difference in the proportion of patients who achieved a PASI of 2 or lower (i.e. virtually disease free) after 12 months of therapy. The authors used the results of a recent RCT in which the two biologics were studied head-to-head, as a baseline to compare the effectiveness data derived from the BADBIR registry.

Findings
A total of 1231 patients were included, 917 receiving ustekinumab (mean age 45 years, 40% female) and the remainder secukinumab (mean age 46 with 38% female). A PASI at 12 months post-treatment was available for only 42% and 45.5% of those given secukinumab and ustekinumab respectively. Secukinumab was superior to ustekinumab in achieving a PASI of 2 (relative risk = 1.28, 95% CI 1.06 – 1.55). However, a further and important finding from the BADBIR registry data was that the estimate of efficacy from the RCT appeared much lower in practice. For example, secukinumab and ustekinumab were 17.5% and 15.1% less effective than the RCT data would suggest.

Commenting on these findings, the authors suggested that given this discrepancy, clinicians should aim to inform patients prescribed either drug that the true effectiveness was likely to be lower than expected based on the results shown in the clinical trial.

Citation
You ZZN et al. Randomised trial replication using observational data for comparative effectiveness of secukinumab and ustekinumab in psoriasis. A study from the British Association of Dermatologists Biologics and Immunomodulators register. JAMA Dermatol 2020