Laura Joszt

The FDA has approved zanubrutinib (Brukinsa), a second-generation Bruton tyrosine kinase (BTK) inhibitor, for the treatment of all patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) regardless of whether or not they are newly diagnosed or have been previously treated, including those who received ibrutinib (Imbruvica).

The approval was based on the findings from 2 phase 3 clinical trials. SEQUOIA (NCT03336333) included 479 patients randomly assigned to receive either zanubrutinib or bendamustine plus rituximab (BR). ALPINE (NCT03734016) randomly assigned 625 patients to either zanubrutinib or ibrutinib, a first-generation BTK inhibitor.

CLL will account for nearly one-third (31.4%) of new leukemia cases in the United States in 2023 (18,740 out of 59,610 new cases), according to statistics from the American Cancer Society.

“We have seen striking data from the Brukinsa development program demonstrating significant and consistent efficacy across CLL patient sub-types, including the high-risk del17p/TP53 mutated population, and regardless of treatment setting,” Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, said in a statement. “With extensive follow-up across the CLL development program and the combined results from the SEQUOIA and ALPINE trials, Brukinsa is established as a new standard of care for CLL.”

In SEQUOIA, the median progression-free survival (PFS) was not reached in the zanubrutinib arm and was 33.7 months in the BR arm. The results were published in The Lancet Oncology.

 Among the 110 patients with previously untreated CLL/SLL with 17p deletion, the overall response rate (ORR) was 88% and the median duration of response was not reached after a median follow-up for 25.1 months.

Recent data from ALPINE were presented December 2022 at the 64th American Society of Hematology (ASH) Annual Meeting and published simultaneously in New England Journal of Medicine.

 Those results highlighted a 35% benefit in PFS for patients receiving zanubrutinib compared with ibrutinib after 2.5 years. Zanubrutinib demonstrated an ORR of 80.4% compared with 72.9% for ibrutinib. The median duration of response was not reached in either arm after a median follow-up of 14.1 months.

Brown presented the ALPINE data at the ASH meeting. “PFS is the gold standard for measuring efficacy in CLL clinical trials,” she said in a statement when the data were released. “The ALPINE data showing superior efficacy and consistent benefit across patient subgroups including

patients with high-risk del(17p)/TP53, along with a favorable cardiovascular safety profile, provide compelling evidence for Brukinsa as a practice-changing [BTK] inhibitor for patients with CLL.”

In a pooled analysis across clinical trials, the most common adverse reactions were decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%). Only 3.7% of patients reported atrial fibrillation or flutter and only 0.2% of patients had grade 3 or higher ventricular arrythmias.

One of the benefits of zanubrutinib over ibrutinib is the favorable benefit-risk profile and the decreased off-target inhibition-related toxicities, according to a study published in Journal of Clinical Oncology.

According to the FDA, the recommended dosage of zanubrutinib is 160 mg taken orally twice daily or 320 mg orally once daily until the patient experiences disease progression or unacceptable toxicity.

Zanubrutinib is already approved to treat adults with Waldenström’s macroglobulinemia, mantle cell lymphoma who have received at least 1 prior therapy, and relapsed or refractory marginal zone lymphoma who have received at least 1 anti-CD20–based regimen. The mantle cell and marginal zone lymphoma indications were both approved under accelerated approval and continued approval may be contingent on confirmatory trials.

“With 4 US approvals in just over 3 years and demonstrated superiority versus ibrutinib in the final progression-free survival analysis of the ALPINE trial, we believe Brukinsa is well-positioned to become the BTK [inhibitor] of choice across multiple indications,” said Mehrdad Mobasher, MD, MPH, chief medical officer, Hematology at BeiGene.

1. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5

2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. Published online December 13, 2022. doi:10.1056/NEJMoa2211582

3. Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: interim analysis of a randomized phase III trial. J Clin Oncol. 2022;JCO2200510. doi:10.1200/JCO.22.00510

Articles

The approval makes zanubrutinib available to all patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) whether they are newly diagnosed or previously treated.

Zanubrutinib Approved in First-line or Relapsed/Refractory CLL/SL

Patients with moderate-to-severe atopic dermatitis (AD) experience an impaired quality of life (QOL) and half of patients have co-existing type 2 inflammatory diseases, according to a study documenting the real-world effectiveness and safety of Dupixent (dupilumab).

Researchers in Germany conducted a national, multicenter, prospective, noninterventional study for the purposes of investigating the safety and effectiveness of Dupixent in the real-world setting. The PROLEAD study collected baseline characteristics of patients to understand how patients are usually treated with Dupixent in Germany.

The results, which only covered the baseline characteristics of patients, were 

. Future publication will report on the effectiveness and safety of Dupixent.

Moderate-to-severe AD is a chronic type 2 inflammatory disease and patients experience frequent disease flares with intense itch and a poor quality of life, the researchers explained. In Germany, only one-third of patients are treated by a specialist; as a result, patients with AD are undertreated and novel therapies, such as Dupixent are rarely prescribed.

The study included 817 patients with baseline data available across 126 sites throughout Germany. The mean age of patients was 43.4 years and 48.5% were female. The majority (66.6%) of patients received their AD diagnosis during childhood and 51.8% had co-existing atopic and type 2 inflammatory diseases.

Regarding burden of disease, the researchers found:

A mean number of 6.1 patient-reported flares in the previous 12 months

Mean number of 2.1 days spent in a hospital as an inpatient over the previous 24 months

Half (50.7%) of patients said their disease “very”, “quite a bit” or “moderately” hampered their ability to practice their profession/their studies/their everyday school life

Nearly all (96.6%) of the patients had received topic treatments previously, 61.4% had received systemic therapy, and 51.3% had previously received ultraviolet/phototherapy. Only 38.6% of patients had never received any systemic therapy prior to receiving Dupixent.

For the 12 months prior to baseline, 43.6% of patients had received only a topic therapy. At baseline, moderate potent or potent topical corticosteroid were the most common treatment given at the same time as Dupixent. However, half (50.4%) of patients had not received any AD treatment with Dupixent at baseline.

The researchers noted that “the number of patients receiving topical and/or systemic treatments for AD decreased towards baseline, with approximately half then receiving dupilumab as monotherapy. Moreover, patients receiving dupilumab became less dependent on combination therapy with systemic and topical AD treatment over time.”

The common reasons to start Dupixent were that topical therapy alone was insufficient (95.1%) and the risk-benefit ratio (42.3%).

Most patients (62.9%) presented with severe AD at baseline and 27.7% had moderate AD. The researchers noted that in terms of skin lesions at baseline, the patients in the real world were “less severely affect by AD” compared with the patients in the pivotal phase 3 CHRONOS trial.

The disease-specific Dermatology Life Quality Index scores at baseline indicated a large impact on QOL and a high burden of AD among the patient population in PROLEAD, the authors noted.

“The results of the present and previous studies investigating dupilumab demonstrate the potential to improve management of moderate-to-severe AD,” they wrote.

This article originally appeared on Managed Heatlhcare Executive.

A national study in Germany identified the baseline characteristics of patients with moderate-to-severe atopic dermatitis (AD) to understand how they are usually treated with Dupixent in the real world.

Impaired Quality of Life, Disease Burden Felt by Patients with Moderate-to-Severe Atopic Dermatitis

Patients on Dupixent (dupilumab) who have controlled atopic dermatitis (AD) can successfully have their dose reduced and maintain stable low disease activity. The findings were published in 

Allergy: European Journal of Allergy & Clinical Immunology

Researchers in the Netherlands evaluated a patient-centered dosing regimen for patients with controlled AD with 90 adults with AD who were treated with Dupixent. Type 2 inflammation is common in atopic diseases, and Dupixent targets key drivers of type 2 inflammation, including interleukin (IL)-4 and IL-13.

“Continuing the standard dosage in patients with persistently controlled AD might lead to overtreatment and an increase in adverse events (e.g. injection side reactions, conjunctivitis),” the researchers noted.

The patient-centered dosing regimen is based on tapering protocols of biologics in other diseases, such as rheumatoid arthritis. In this study, patients were eligible for their dose to be reduced after being treated with Dupixent for 52 weeks and when disease activity was controlled, which was defined as Eczema Area and Severity Index (EASI) score of 7 or less.

For patients with EASI ≤ 7, their dosage interval was prolonged to every 3 weeks, which reduced dosage to 66% of the standard dosage. Patients who continued to have controlled disease activity then prolonged interval to every 4 weeks (double the original interval), which reduced dosage to 50% of the standard dosage. Patients with persistently controlled disease reduced their dosage even more to every 6 weeks, and finally to every 8 weeks. The dosage interval was shortened for patients with increased pruritus scores or physician-reported disease severity scores.

After 52 weeks of treatment, patients were divided into 3 groups:

Group A was patients with uncontrolled disease or those who wanted to continue their dosing and did have not their dose reduced.

Group B prolonged their dose interval to every 4 weeks

Group C prolonged dose interval to every 6 weeks or every 8 weeks

The patients were followed up for at least 91 weeks. The mean age of patients was 42.4 years, and the majority were male (65.6%). During the first 52 weeks of treatment with Dupixent, the median EASI score dropped from 17.9 at baseline to 2.7.

Group A maintained stable disease severity with a median EASI score of 6.4 after 52 weeks and 5.4 after a mean duration of 115 weeks. At 52 weeks, 50% had controlled AD; at 85 weeks, 40% had controlled AD; and at 115 weeks, 50% had controlled AD.

Groups B and C also maintained stable disease with no significant difference in EASI score between 52 weeks, when the tapering started, and the end of the study (mean 141 weeks for Group B and 140 weeks for Group C). After at least 3 months on a dosage interval of every 4 weeks, 83.3% of patients in group B and 86.7% of patients in group C had controlled AD. At the end of the study, when patients in group C had moved to dosing every 6 or 8 weeks, 93.3% of patients had controlled AD.

Numeric Rating Scale (NRS) pruritus temporarily increased after prolonging the dosing interval, but these changes were small and scores remained low, the researchers noted. “The clinical relevance of these differences are questionable as the changes in NRS scores were small and inconsistent and median NRS scores remained ≤4, which is also considered as a treatment target,” they wrote.

One of the limitations noted was that more research is needed to understand unsuccessful dose reduction because patients who shortened their intervals were not included. In addition, a direct comparison between patients on standard dosing and dose reduction is not feasible since patients in group A who did not have their dose tapered had higher disease severity scores than patients in groups B and C.

“These findings are the first step toward personalized dupilumab treatment for controlled AD patients in clinical practice,” the authors concluded.

Patients with persistently controlled atopic dermatitis who had their doses reduced were able to maintain their low disease activity.

Atopic Dermatitis Remains Controlled Even After Reduction of Dupixent Dose

Clinical trials of Dupixent (dupilumab) in patients with asthma, chronic rhinosinusitis with nasal polyps (CRwNP) and atopic dermatitis (AD) has identified temporary increases in blood eosinophil counts. However, these increases had no effect on the efficacy of Dupixent, researchers found.

The Journal of Allergy and Clinical Immunology: In Practice

The increases in eosinophil counts seen in trials often happen in the first few weeks of treatment before returning to baseline or even lower. The researchers gathered data from 11 trials of Dupixent in adults and adolescent patients. There were 6642 patients analyzed, of which 3145 had AD, 2876 had asthma, 574 had CRSwNP, and 47 had eosinophilic esophagitis (EoE).

For the asthma trials, the researchers identified transient increases in eosinophils in the QUEST, DRI, and VENTURE studies among patients taking Dupixent but not the placebo groups. Eosinophils had risen by week 4 of the study for patients on Dupixent while counts remained at baseline levels for the placebo group. Those elevated counts generally decreased starting at week 24.

Patients in these 3 studies could continue on in TRAVERSE. In the extension study, patients had taking Dupixent in QUEST continued on the drug and their eosinophil counts continued to decline. However, patients on placebo in QUEST who transitioned to Dupixent had no increase in eosinophil counts. Patients rolling into TRAVERSE from DRI had a 16-week gap. Both patients who had been on placebo in DRI and those on Dupixent had an increase in eosinophil counts from baseline to week 4. The increase was resolved by week 24. Finally, patients continuing from VENTURE who were on Dupixent had a decline in counts while those on placebo initially had an increase from baseline to week 24 before declining and reaching baseline levels by week 96.

In trials for CRSwNP, patients taking Dupixent in SINUS-24 and SINUS-52 also had higher mean eosinophil counts compared with placebo. Elevated counts were observed at week 16 before decreasing starting at week 24. By the end of SINUS-52, counts were below baseline.

In AD, there was a slight increase in eosinophil counts for patients taking Dupixent starting as early as week 4 in SOLO-1 and SOLO-2; however, counts had declined to baseline by week 8. In CHRONOS there was a slight increase in eosinophils by week 8, but this dropped to or below baseline starting with week 12.

The researchers reported no increase in eosinophil counts for patients with EoE in Dupixent trials. However, the authors noted that there were a limited number of patients in the EoE and “data from larger-scale phase 3 studies remain to be assessed.”

Overall, the temporary increase in eosinophil counts were rarely associated with any clinical symptoms or sequelae. Patients with asthma and CRSwNP saw their counts either return to baseline or below baseline after the first 24 weeks. In AD, patients had transient increases that were not reflected in median fold-change from baseline, “indicating that these increases were generally observed in patients with higher baseline eosinophil counts,” the authors wrote.

They suggested a need for additional studies to better understand why responses differed among the disease, particularly in AD compared with the airway diseases. They also noted that Dupixent’s efficacy, based on these results, is not linked to changes in blood eosinophil counts. Instead, the drug’s efficacy is related to blocking interleukin (IL)-4 and IL-13 signaling.

“While these increases are mostly transient, clinician discretion should be used to monitor patients suspected of having an eosinophilic condition,” the authors concluded.

This article appeared on Managed Healthcare Executive.

The increases had no impact on the efficacy of the drug and were rarely associated with symptoms or sequelae.

Temporary Increase in Eosinophil Levels Found in Patients Using Dupixent

Patients with atopic dermatitis (AD) reported more problems related to symptoms and quality of life during the COVID-19 pandemic, according to multiple measurement tools. The findings were 

Researchers evaluated four measurement tools: the EuroQol-5 Dimension 5-level version (EQ-5D-5L), Skindex-16, Dermatology Life Quality Index (DLQI) and DLQI Index-Relevant (DLQI-R), a recently proposed scoring formula of the DLQI for avoiding possible bias in the “not relevant” response option. In addition to testing the measurement properties of these measures in adults with AD using a cross-sectional survey, they compared health-related quality of life (HRQOL) in these patients before and since the start of the pandemic.

The cross-sectional survey was carried out in Hungary and involved 2 academic dermatology clinics. Data was collected from March 2018 to March 11, 2020 (before COVID-19) and June 2020 to January 2021 (since COVID-19). Patients completed EQ-5D-5L, DLQI/DLQI-R, Skindex-16, a 0- to 10-item assessment for self-reported severity and questions about the history of their disease as well as their sociodemographic information. Dermatologists completed a second section with clinical information the Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI) and objective SCORing Atopic Dermatitis (oSCORAD).

A total of 218 patients completed the questionnaire. The mean age was 31.3 years and the majority (57.8%) were women. Thirty-five patients had dermatologic comorbidities and 194 had nondermatologic condition(s). According to the responses, 9.6% of patients were untreated, 63.3% were on systemic (nonbiologic) therapy, 23.4% were on topical therapy, 2.3% were on biological therapy and 1.4% were receiving phototherapy.

EASI identified 22.1% of patients having severe AD compared with 45.6% with oSCORAD, and 21.2% according to IGA. Severity scores did not differ significantly before and since COVID-19. While there were no significant differences in total HRQOL scores before and since COVID-19, more patents reported problems in specific areas.

Since COVID-19, more patients reported pain/discomfort (73.1% vs 60.0%) and anxiety/depression (55.9% vs 49.6%) on the EQ-5D-5L. On the DLQI, more patients reported problems with shopping/home/garden (82.8% vs 53.6%) and working/studying (72.8% vs 64.8%) since COVID-19. On Skindex-16, more patients reported problems with hurting (84.9% vs 75.6%), persistence/recurrence of AD (98.9% vs 91.9%), worry (97.8% vs 92.7%) and interactions with others (80.0% vs 72.8%) since COVID-19.

According to the authors, patients who had more severe disease had worse HRQOL across all outcome measures. However, they noted that patients with AD in the sample had quite severe overall HRQOL impairment both before and during the pandemic with a relatively high average DLQI even among the patients who had clear or mild AD.

“Based on our study, Skindex-16, DLQI, and DLQI-R also have good convergent and known-group validity in AD that make them appropriate instruments for HRQOL assessment in both clinical and research settings,” they noted.

One of the limitations was that given where they recruited from, the patients with moderate and severe AD may have been overrepresented compared with patients with mild AD. Another limitation was that AD-specific questionnaires could not be used because they do not have a Hungarian version.

Given the strong performance of EQ-5D-5L, DLQI, DLQI-R and Skindex-16 against validity tests, the authors suggested they “may be used as standalone measures or to complement AD-specific HRQOL instruments in clinical trials and daily practice.”

This article originally appeared on Managed Healthcare Executive.

Certain problems related to health-related quality of life (HRQOL) became more common among patients with atopic dermatitis since the start of the COVID-19 pandemic.

Atopic Dermatitis Patients See Decline in HRQOL Since Pandemic's Start

Results gathered from clinical trials do not always reflect the real-world patient population, but a new study using an electronic medical record (EMR) database has found that patients treated with Dupixent (dupilumab) in the real world achieved outcomes consistent with clinical trials.

The researchers sought to evaluate the real-world effectiveness of Dupixent in adults with moderate-to-severe atopic dermatitis (AD) over a time period that was comparable to clinical trials of Dupixent. The findings were 

While there have been other real-world studies on the effectiveness of Dupixent, they were either in small populations or from a limited number of study sites, the authors noted.

They used the Modernizing Medicine’s Electronic Medical Assistant (EMA) dermatology-specific EMR database, which contains structured, real-world data from more than 30% of the dermatologists in the United States. This database allowed the researchers to extract AD assessments, such as severity based on the six-point Investigator Global Assessment (IGA) scale (0 = clear to 5 = very severe), itch severity based on a numerical rating scale (NRS; 0 – no itch to 10 = most severe itch) and body surface area (BSA) affected.

There was a total of 1,466,601 patients with AD in the database, of which 22,914 were initiated on Dupixent during the study. After applying the inclusion criteria, there were 3 different cohorts, which partially overlapped:

The mostly widely used therapy prior to the index date was topical corticosteroids in 77.0% in the IGA cohort, 83.0% in the NRS cohort and 72.4% in the BSA cohort.

After 4 months of Dupixent, 72.0% of patients in the IGA cohort saw their score improve to ≤ 2 including 42.8% who achieved a score of IGA 0/1. At baseline, 41.6% of patients in this cohort had an IGA score of 3 and 58.4% had a score of 4/5.

Among the NRS cohort, the mean score was reduced to 2.8 after four months of treatment down from a mean score of 7.0 prior to starting Dupixent. “This reduction was driven by a shift in distribution from higher severity levels during the pre-index period, with 70.5% reporting scores in the ‘mild range’ at month 4, including almost one-quarter of the patients (24.1%) with no itch,” the authors wrote.

There was also a significant reduction in BSA affected. During the pre-index period, the reported BSA was 39.3%, which dropped to 16.3% after four months of treatment with Dupixent. When stratified by age, sex and treatment history, there were similar reductions observed.

“On all outcomes, the results showed that the majority of patients achieved benefits after initiation of dupilumab therapy that were statistically significant, clinically meaningful, and consistent with improvements in AD observed at similar time points in the dupilumab clinical trials and other real-world studies,” the authors wrote.

They noted several limitations. First, the data evaluated in the study are optional fields in EMRs and only a small proportion of patients had these data elements recorded both prior to and after initiating Dupixent. In addition, while clinical trials assessed itch severity using the average of daily scores for a week, this study only used a single time point.

Ultimately, the researchers reported that the study corroborated the findings from Dupixent clinical trials.

“These results showed that, in adults with moderate-to-severe AD treated with dupilumab in routine clinical practice, significant and clinically meaningful improvements in clinician-assessed global AD severity were consistently achieved by the majority of patients, with significant and substantial reductions in patient-reported itch severity as well as in BSA affected,” they concluded.

This article was originally published by Managed Healthcare Executive.

Eichenfield LF, Armstrong A, Guttman-Yassky E, et al. Real-world effectiveness of dupilumab in atopic dermatitis patients: analysis of an electronic medical records dataset. 

. 2022 May 11. doi: 10.1007/s13555-022-00731-z.  Online ahead of print. 

Data gathered from an electronic medical record found the results in a real-world patient population with atopic dermatitis were consistent with those found in clinical trials.