On December 7, 2020 CIBMTR reported that Initial results from a recent study indicate that for patients between the ages of 50 and 75, overall survival nearly doubled when patients with myelodysplastic syndrome (MDS) received allogeneic hematopoietic cell transplantation (alloHCT) when compared to other treatments (Press release, CIBMTR, DEC 7, 2020, View Source [SID1234572361]). Additionally, patients age 65 and older saw a similar benefit to overall survival as those between the ages of 55 and 64. The majority of patients received transplant using matched unrelated donors, and outcomes were similar to those of patients using matched related donors.

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These findings from a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) study were presented during the 62nd ASH (Free ASH Whitepaper) Annual Meeting & Exposition.

The initial results of a separate observational study currently being run by the CIBMTR (Center for International Blood and Marrow Transplant Research)—which is a research collaboration between the National Marrow Donor Program (NMDP)/Be The Match and the Medical College of Wisconsin—also demonstrate the patients 65 and older experience similar benefit from allogeneic HCT to patients 55-64 years of age. In addition, the initial analysis of the CIBMTR observational study showed similar non-relapse mortality between these two age groups. The initial results were published in JAMA Oncology.

"In both studies of older adults with MDS, we found that transplantation using either an HLA-matched related or HLA-matched unrelated donor is feasible even in older patients and in the BMT CTN study, provides significant survival benefit relative to non-transplant therapies. This supports the early referral of all patients with MDS to a transplant center for consultation, regardless of age," said Steven Devine, MD, Chief Medical Officer, NMDP/Be The Match, and Associate Scientific Director, CIBMTR.

Early referral to a transplant center for all patients is critical as it allows the search for a donor to start early for those patients who are eligible for transplant. This increases the likelihood a patient will find a suitable donor and proceed to transplant earlier in their disease, which can lead to better outcomes.

"While alloHCT is the only known cure for MDS, many older adults did not receive HCT in the past because the benefits for older adults had not been sufficiently proven for CMS to provide payment coverage. Taken together, these studies support allogeneic HCT for older patients with MDS based on survival improvements," said J. Douglas Rizzo, MD, MS, Senior Scientific Director, CIBMTR.

Currently, the Centers for Medicare and Medicaid Services (CMS) does not cover alloHCT for adults over age 65 unless the patient is enrolled in a qualified Coverage with Evidence Development (CED) study. The NMDP/Be The Match and CIBMTR will provide CMS with the data from these two studies for its use in making coverage policy decisions.

In the meantime, the current CIBMTR observational study meets CED requirements and qualifies for payment under CMS. The study remains open for enrollment for a broad range of clinically eligible Medicare recipients. By enrolling patients in this study, more older patients across the U.S. with MDS will have access to HCT.

Access the BMT CTN study abstract presented by senior study author Corey Cutler, MD, MPH, Dana-Farber Cancer Institute, during the ASH (Free ASH Whitepaper) Annual Meeting:

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

Access the initial results of the CIBMTR observational study published in JAMA Oncology:

Comparison of Patient Age Groups in Transplantation for Myelodysplastic Syndrome: The Medicare Coverage With Evidence Development Study

About the BMT CTN

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducts rigorous multi-institutional clinical trials of high scientific merit, focused on improving survival for patients undergoing hematopoietic cell transplantation and/or receiving cellular therapies. The BMT CTN has completed accrual to 43 Phase II and III trials at more than 100 transplant centers and enrolled over 12,800 study participants. BMT CTN is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, a part of the National Institutes of Health (NIH) and is a collaborative effort of 20 Core Transplant Centers/Consortia, the CIBMTR (Center for International Blood and Marrow Transplant Research), the National Marrow Donor Program/Be The Match and the Emmes Company, LLC, a clinical research organization.

On December 7, 2020 Paige, a global leader in AI-based digital diagnostics, reported that it will present new data evaluating Paige Breast Alpha, a machine learning system designed to detect breast cancer in digital images of breast tissue, at the upcoming 2020 San Antonio Breast Cancer Symposium (SABCS 2020), taking place virtually December 8-11, 2020 (Press release, Paige AI, DEC 7, 2020, View Source [SID1234572360]).

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For pathologists reviewing breast tissue slides under the microscope, the large volume of slides can pose significant challenges for workload management and pathologist productivity. The poster, "Clinical-grade detection of breast cancer in biopsies and excisions using machine learning," will be featured during a spotlight poster discussion, which highlights some of the most noteworthy and groundbreaking research submitted to the conference.

The poster abstract is available online and viewing details are below:

Clinical-grade detection of breast cancer in biopsies and excisions using machine learning
Authors: Hanna MG, et al.
Session: Spotlight Poster Discussion 6 | Thursday, December 10, 2020 | 3:30pm – 4:45pm CST
Poster #: PD6-03

On December 7, 2020 MaaT Pharma reported positive updated clinical results from its lead full-ecosystem microbiome restoration biotherapeutic, MaaT013, at the virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, MaaT Pharma, DEC 7, 2020, View Source [SID1234572359]). The data stems from a compassionate use/expanded access treatment program in France called Autorisation Temporaire d’Utilisation Nominative (ATUn), using MaaT013 to treat patients that developed acute Graft-versus-Host-Disease with GI involvement (GI aGvHD) following allogeneic hematopoietic cell transplantation (allo-HCT) and were refractory to multiple lines of treatments, including corticosteroids. Treatment with MaaT013 was well tolerated and provided encouraging signs of efficacy with a 6-month overall survival of 52%, demonstrating the positive impact microbiome restoration can achieve in heavily pre-treated patients. The results were presented by leading hemato-oncological expert Florent Malard, MD, PhD, Associate Professor of Hematology at Saint-Antoine Hospital and Sorbonne University, in an oral presentation on December 6, 2020 at the virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"Acute GvHD is a devastating disease where the transplant donor’s immune cells attack the patient’s tissue following allo-HCT and to date these patients have limited treatment options and a very low long-term survival rate when steroid-refractory," said Dr Florent Malard MD, PhD, Associate Professor of Hematology at Saint Antoine Hospital in Paris. "These data are very encouraging and we are continuing to see clinical benefits in the larger cohort of patients treated with MaaT Pharma’s microbiome restoration therapeutic. The very good overall response observed represents a promising and important step towards providing an effective treatment option for these patients."

In the presented data update, 29 recipients of allo-HCT that progressed to steroid-dependent or steroid refractory aGvHD (22, classical aGvHD; 2, late-onset aGvHD; 5, aGvHD with overlap syndrome) and had failed 1 to 5 lines (median: 3) of systemic treatments were evaluated after treatment with MaaT013. Each patient received a median of three doses of MaaT013 (range, 1-3) and treatment-based responses were observed seven days after each administration and 28 days after administration of the first dose. Nine patients achieved a complete response (CR), 6 a very good partial response (VGPR), and 2 a partial response (PR) at day 28. All 9 patients with a complete response were still alive at the last follow-up (median FU: 444 days (197-654)), suggesting an extended survival in comparison to historic cohorts. In addition, these patients were able to taper or stop steroids as well as immunosuppressants. Notably, 15 patients were still alive at last follow-up (median FU: 313 days (28-654)) and the 6-month and 12-month overall survival were 52% and 46%, respectively. Overall, the data revealed that restoring the microbiome with a full-ecosystem microbiota restoration biotherapeutic provided a positive impact for a majority of the patients and the safety of MaaT013 was satisfactory for all patients.

"These additional positive data from the compassionate use program further support the potential of MaaT Pharma’s products, targeting restoration of a functional gut to treat severe and life-threatening diseases," said John Weinberg, MD, Chief Medical Officer of MaaT Pharma. "Seeing the clinical benefit of MaaT013 together with its continued tolerability profile, we believe that our approach can truly make a difference for aGvHD patients. Additionally, we expect the readout from HERACLES, our fully enrolled Phase 2 trial of MaaT013 in steroid-refractory, GI-predominant aGvHD patients, early next year. This will provide a more complete picture of the potential of our product across clinical settings."

About MaaT013

MaaT013 is a full-ecosystem, off-the-shelf, standardized, pooled-donor, high-richness microbiome biotherapeutic in enema formulation. The product has a stability of up to 24 months and is characterized by a high diversity and consistent richness of microbial species. MaaT013 has been granted Orphan Drug Designation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). MaaT013 is currently being investigated in a Phase 2 clinical trial (NCT03359980) to evaluate its safety and efficacy in steroid-refractory, GI aGvHD patients.

On December 7, 2020 Precigen, Inc., a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported at the 62nd ASH (Free ASH Whitepaper) Annual Meeting and Exposition (Abstract 2864) clinical progress and new data from the ongoing Phase 1/1b clinical study of PRGN-3006 UltraCAR-T in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS) (clinical trial identifier: NCT03927261) (Press release, Precigen, DEC 7, 2020, View Source;prgn-3006-ultracar-t-at-the-62nd-ash-annual-meeting-and-exposition-301186957.html [SID1234572358]).

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AML is a rapidly progressing disease with poor prognosis and high unmet need. Precigen’s UltraCAR-T platform is designed to overcome limitations of currently available chimeric antigen receptor (CAR)-T therapies by utilizing an advanced overnight non-viral gene delivery manufacturing process at a medical center’s cGMP facility without the need for ex vivo expansion. Current CAR-T cell therapies are limited due to, inter alia, the prolonged interval between apheresis to product infusion and an exhausted phenotype of T cells resulting from lengthy ex vivo expansion. As announced in November 2020, UltraCAR-T cells for the PRGN-3006 study are now manufactured overnight using Precigen’s proprietary UltraPorator device. PRGN-3006 UltraCAR-T is a multigenic autologous CAR-T simultaneously expressing a CAR specifically targeting CD33; membrane bound IL-15 (mbIL15) for enhanced in vivo expansion and persistence; and a kill switch to conditionally eliminate CAR-T cells for an improved safety profile. CD33 is over-expressed on AML blasts with lesser expression on normal hematopoietic stem cells.

An investigator-initiated, non-randomized Phase 1/1b dose-escalation study to evaluate the safety and maximal tolerated dose of PRGN-3006 UltraCAR-T is currently ongoing in collaboration with the H. Lee Moffitt Cancer Center & Research Institute (Moffitt). The study population includes adult patients (≥ 18 years) with r/r AML and hypomethylating agent (HMA) failure, higher risk MDS or chronic myelomonocytic leukemia (CMML) patients with ≥ 5% blasts. To test the hypothesis that expression of mbIL15 on PRGN-3006 can promote UltraCAR-T cell expansion and persistence without the need for lymphodepletion and improve the overall safety profile, study subjects receive the PRGN-3006 infusion either without prior lymphodepletion (Cohort 1) or following lymphodepleting chemotherapy (Cohort 2). A multicenter expansion of the trial is planned.

Key findings:

At the data cutoff (November 10):
Six patients have been treated across the two lowest dose levels in Cohort 1 (no lymphodepletion):
N=3 at Dose Level 1 (3 x 104 – ≤ 1 x 105 UltraCAR-T cells/kg); Total 1.8 to 7 x 106 UltraCAR-T cells
N=3 at Dose Level 2 (1 x 105 – ≤ 3 x 105 UltraCAR-T cells/kg); Total 24 to 29 x 106 UltraCAR-T cells
Three patients have been treated at the lowest dose level in Cohort 2 (with lymphodepletion):
N=3 at Dose Level 1 (3 x 104 – ≤ 1 x 105 UltraCAR-T cells/kg); Total 4.9 x 106 to 1 x 107 UltraCAR-T cells
Encouraging expansion and persistence of PRGN-3006 UltraCAR-T was observed in both lymphodepletion and non-lymphodepletion cohorts and across all dose levels.
PRGN-3006 has been safe and well-tolerated with no dose limiting toxicities (DLTs), no neurotoxicity, and a low incidence of treatment-related adverse events (TRAEs) and serious adverse events (SAEs). A few treatment-related SAEs have been observed, including transient grade 1-3 cytokine release syndrome (CRS), which is more indicative of the biologic activity of the cells.
There has been a 100% manufacturing success rate using the UltraCAR-T manufacturing process.
A case study of the patient with the longest follow-up as of the data cutoff was also presented. This patient received, one day after gene transfer and without prior lymphodepletion, a very low dose, approximately three hundred thousand UltraCAR-T per kilogram (3 x 105 UltraCAR-T/kg) for a total of only 24 million UltraCAR-T. She is a 69 year old female with secondary AML (sAML) and four prior lines of therapy, including induction chemotherapy (IC), allogenic hematopoietic stem cell transplantation (allo-HSCT), HMA plus venetoclax (HMA+VEN), refractory to all therapy post allo-HSCT. The patient had approximately 40% peripheral blasts and 47% bone marrow blasts at baseline.

Case study findings:

After a very low dose infusion without prior lymphodepletion, PRGN-3006 UltraCAR-T cells demonstrated robust expansion and persistence in blood at seven months post-infusion at the time of the most recent sample collection (see FIGURE 1).
UltraCAR-T cells demonstrated trafficking to bone marrow and the ability to expand and persist in bone marrow.
The patient showed a decline in blast levels in blood and bone marrow concomitant with UltraCAR-T expansion and persistence (see FIGURE 1) and had stable disease. Patient follow-up is ongoing.
"There is an urgent need for novel therapies for relapsed or refractory AML patients as the median overall survival for this patient population is less than six months. Current CAR-T approaches for AML have faced challenges due to long manufacturing durations resulting in subsequent delays in treatment," said David A. Sallman, MD, of Moffitt and lead investigator for the PRGN-3006 clinical study. "We are encouraged by the initial data, including safety and manufacturing success from patients treated with autologous UltraCAR-T cells, which were manufactured on-site with almost instant turnaround. We are excited by the expansion and continued persistence of PRGN-3006 UltraCAR-T cells in the patient case study for over seven months post-infusion without prior lymphodepletion and are looking forward to higher doses in the lymphodepleted and non-lymphodepletion cohorts."

"Currently commercialized CAR-T therapies have not demonstrated the persistence needed to drive sustained, durable responses," said Helen Sabzevari, PhD, President and CEO of Precigen. "The results from Dr. Sallman’s patient case study are particularly encouraging as the patient received a very low dose of cells without any ex vivo expansion or activation and no lymphodepletion, which highlights the importance of membrane bound IL-15 in expansion and persistence of these cells and, we believe, differentiates the UltraCAR-T platform from other CAR-T’s. In particular, expansion and persistence of UltraCAR-T cells in the patient’s blood through seven months post-infusion show promise for the durability of PRGN-3006. We look forward to providing additional details for the PRGN-3006 study at our upcoming clinical update call this month."

About Acute Myeloid Leukemia (AML)
AML is a cancer that starts in the bone marrow, but most often moves into the blood.1 Though considered rare, AML is among the most common types of leukemia in adults.2 In 2019, it was estimated that 21,450 new cases of AML would be diagnosed in the US.2 AML is uncommon before the age of 45 and the average age of diagnosis is about 68.2 The prognosis for patients with AML is poor with an average 5–year survival rate of approximately 25 percent overall, and less than a 5 percent 5–year survival rate for patients older than 65.3 Amongst elderly AML patients (≥ 65 years of age), median survival is short, ranging from 3.5 months for patients 65 to 74 years of age to 1.4 months for patients ≥ 85 years of age.3

About Myelodysplastic Syndrome (MDS)
MDS are diseases of the bone marrow generally found in adults in their 70s.4 Incidence in the US is not known for sure, but estimates range from 10,000 each year and higher.4 Using International Prognostic Scoring System (IPSS-R), median survival for MDS patients can vary from less than one year for the "very high" IPSS-R risk group to more than eight years for the "very low" IPSS-R group.4

About PRGN-3006 UltraCAR-T
PRGN-3006 UltraCAR-T is a multigenic autologous CAR-T cell treatment utilizing Precigen’s non-viral Sleeping Beauty system to simultaneously express a CAR specifically targeting CD33, which is over expressed on acute myeloid leukemia blasts with lesser expression on normal hematopoietic stem cell populations and minimal non-hematopoietic expression; membrane bound IL-15 for enhanced in vivo expansion and persistence; and a kill switch to conditionally eliminate CAR-T cells for an improved safety profile. PRGN-3006 is being evaluated in collaboration with the Moffitt Cancer Center in a nonrandomized, investigator–initiated Phase 1/1b dose escalation study to evaluate the safety and maximal tolerated dose of PRGN–3006 UltraCAR-T (clinical trial identifier: NCT03927261). The study population includes patients with relapsed or refractory acute myeloid leukemia or higher risk myelodysplastic syndrome. The US Food and Drug Administration (FDA) has granted orphan drug designation (ODD) for PRGN-3006 UltraCAR-T in patients with AML.

On December 7, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative medicines worldwide, reported that clinical data on its BTK inhibitor BRUKINSA (zanubrutinib) in two posters at the 62nd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, including results from a Phase 2 trial in patients with relapsed/refractory (R/R) B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib and the first results from a pivotal Phase 2 trial in patients with R/R Waldenström’s Macroglobulinemia (WM) that were included in a supplemental new drug application of BRUKINSA currently under priority review in China (Press release, BeiGene, DEC 7, 2020, View Source [SID1234572357]).

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"Tolerability of treatments for B-cell malignancies is an important consideration with BTK inhibition, and BRUKINSA was designed with that in mind to maximize BTK occupancy and minimize off-target effects. Following on the results of the Phase 3 ASPEN trial, in which BRUKINSA demonstrated advantages in safety and tolerability compared to ibrutinib in patients with WM, we’re excited to learn from the Phase 2 trial that BRUKINSA was tolerable and showed activity in patients who discontinued treatment with ibrutinib and/or acalabrutinib due to adverse events," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "Additionally, we reported data from our pivotal Phase 2 trial in China in patients with relapsed/refractory WM, which showed deep responses in a difficult-to-treat patient population. With a growing clinical development team across the globe, we look forward to continuing to advance our clinical program for BRUKINSA."

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual booth at this year’s ASH (Free ASH Whitepaper) Annual Meeting at View Source

Phase 2 Trial of Zanubrutinib in Patients with Previously Treated B-Cell Malignancies Intolerant to Ibrutinib and/or Acalabrutinib

Abstract 2947

This single-arm, open-label, multicenter Phase 2 trial in the U.S. (NCT04116437) was designed to evaluate the safety and efficacy of BRUKINSA in patients with previously treated B-cell malignancies who were intolerant to prior treatment with ibrutinib and/or acalabrutinib. The primary endpoint of safety was assessed by the recurrence and the change in severity of adverse events (AEs) compared to patients’ intolerance AE profile to ibrutinib and/or acalabrutinib. Secondary endpoints included investigator-assessed overall response rate (ORR), investigator-assessed progression-free survival (PFS) and patient-reported outcomes. A total of 60 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), WM, mantle cell lymphoma (MCL) or marginal zone lymphoma (MZL) intolerant to ibrutinib and/or acalabrutinib were enrolled in this trial.

"BTK inhibitors are an emerging standard of care in B-cell malignancies, but off-target effects have been implicated in adverse events – the most common reason for treatment discontinuation. Data from 32 evaluable patients in this trial demonstrated that some intolerable adverse events that patients experienced on other BTK inhibitors did not recur with zanubrutinib treatment, and that it was generally well-tolerated among these patients," commented Mazyar Shadman, M.D., MPH, Associate Professor of Clinical Research Division at Fred Hutchinson Cancer Research Center and Assistant Professor of Oncology at University of Washington.

At the data cutoff on August 28, 2020, with a median zanubrutinib exposure of 3.5 months, safety results from 32 evaluable patients included:

In 32 patients previously treated with and intolerant to ibrutinib, there were 66 intolerant events, 58 (88%) of which did not recur with zanubrutinib treatment; of the eight intolerant events that recurred, seven recurred at a lower grade in severity and one at the same grade;
In two patients previously treated with and intolerant to acalabrutinib, there were four intolerant events, two of which did not recur (both arthralgia) with zanubrutinib treatment; of the two intolerant events that recurred, one recurred at a lower grade in severity and one at the same grade;
Of the 25 Grade 3 intolerant events on ibrutinib and/or acalabrutinib, 23 did not recur with zanubrutinib treatment;
Of the four Grade 4 intolerant events, which were neutropenia (n=2), increased alanine aminotransferase (ALT) (n=1), and increased aspartate aminotransferase (AST) (n=1), none recurred with zanubrutinib treatment;
26 patients experienced at least one AE of any grade on zanubrutinib, with the most common (≥10.0%) being myalgia (21.9%), contusion (18.8%), cough (15.6%), dizziness (15.6%), and fatigue (12.5%);
Eight patients experienced bleeding events on zanubrutinib, all in low-grade severity;
Atrial fibrillation did not recur in six patients who were intolerant to ibrutinib due to atrial fibrillation. Atrial fibrillation and flutter recurred in one patient (3.1%) who was previously treated with and intolerant to ibrutinib at a lower severity (Grade 2 on zanubrutinib vs. Grade 3 on ibrutinib) with a shorter duration (3 days on zanubrutinib vs. 14 days on ibrutinib);
Three patients experienced at least one Grade ≥3 AE, including neutropenia (n=2) and syncope (n=1); and
No serious adverse events (SAEs) or treatment discontinuation due to AEs were reported.
Among the 18 patients who were evaluable for response at the time of data cutoff (13 for CLL, 4 for SLL and 1 for MCL), 17 maintained (n=8) or improved (n=9) responses on zanubrutinib. With the median time to first response being 12.6 weeks, the ORR was 50%, including six (33.3%) PRs and three (16.7%) PRs with lymphocytosis.

Pivotal Phase 2 Trial of Zanubrutinib in Patients with R/R WM in China

Abstract 2940

Data from this single-arm, open-label, multicenter, pivotal Phase 2 trial (NCT03332173) showed that R/R WM patients in China were able to achieve deep, quick, and durable responses on zanubrutinib. A total of 44 patients were enrolled in the trial, including 20 with high risk and 13 with intermediate risk based on WM prognostic scoring, and 43 patients were evaluable for efficacy.

"From the results of the BGB-3111-210 trial, we were encouraged to see a major response rate of nearly 70 percent and a median time to major response under three months, which means zanubrutinib was able to quickly induce deep responses in these WM patients, most of whom were determined to have intermediate to high risks based on the prognostic score," said Lugui Qiu, M.D., Director at Department of Lymphoma in Chinese Academy of Medical Sciences Blood Diseases Hospital and leading Principal Investigator of the trial. "Zanubrutinib also demonstrated a safety profile consistent with previous reports in WM. We hope this BTK inhibitor will become a new effective treatment option for WM patients in China in the near future."

At the data cutoff on August 31, 2019, 27 patients remained on study treatment. With a median follow-up time of 18.58 months, results included:

Major response rate (MRR), defined as partial response or better, was 69.8% (95% CI: 53.9, 82.8), including 32.6% very good partial responses (VGPRs) and 37.2% partial responses (PRs); ORR, defined as minor response or better, was 79.1% (95% CI: 64.0, 90.0);
The median time to VGPR and overall response was 2.87 months and 2.76 months, respectively;
Median progression free survival (PFS) and duration of major response (DOMR) were not reached;
The most common (≥20.0%) treatment-emergent adverse events (TEAEs) of any grade were decreased neutrophil count (56.8%), decreased platelet count (29.5%), decreased white blood cell count (27.3%), upper respiratory tract infection (27.3%), diarrhea (25.0%), weight increase (20.5%), and arthralgia (20.5%);
72.7% of patients experienced at least one Grade ≥3 TEAE, with the most common (≥10.0%) being decreased neutrophil count (31.8%), decreased platelet count (20.5%), lung infection (13.6%), and decreased white blood cell count (11.4%);
50.0% of patients experienced at least one serious TEAE and 11.4% of patients discontinued treatment due to TEAEs; and
4.5% of patients experienced a fatal TEAE, with one patient caused by multiple organ dysfunction syndrome and acute hepatitis B, and the other one being death with unknown reason, which was considered by investigator to be caused by progression of WM and accompanying respiratory failure.
About BRUKINSA (zanubrutinib)

BRUKINSA (zanubrutinib) is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK), discovered by BeiGene scientists, that is currently being evaluated globally in a broad pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

BRUKINSA was approved by the U.S. FDA in November 2019 to treat adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

BRUKINSA was approved in China in June 2020 for the treatment of MCL in adult patients who have received at least one prior therapy and the treatment of CLL/SLL in adult patients who have received at least one prior therapy. A supplemental new drug application (sNDA) of BRUKINSA in patients with relapsed/refractory Waldenström’s macroglobulinemia (WM) has been accepted by the Center for Drug Evaluation (CDE) of the NMPA and is currently under priority review.

A marketing authorization application (MAA) for BRUKINSA for the treatment of patients with WM who have received at least one prior therapy or as first-line treatment for patients unsuitable for chemo-immunotherapy has been accepted by the European Medicines Agency (EMA).

In addition, multiple regulatory filings of BRUKINSA have been accepted in other countries and are currently under review.

BRUKINSA is not approved outside of the United States and China.

IMPORTANT U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%), and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For co-administration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.