On December 7, 2024 Amgen (NASDAQ:AMGN) reported new data demonstrating that adding BLINCYTO (blinatumomab) to chemotherapy significantly improves disease-free survival (DFS) in newly diagnosed pediatric patients with National Cancer Institute (NCI) standard risk (SR) B-cell acute lymphoblastic leukemia (B-ALL) of average or higher risk of relapse (Press release, Amgen, DEC 7, 2024, View Source [SID1234648863]). The data are from a Phase 3 study (AALL1731) conducted by the Children’s Oncology Group. The results were simultaneously published in the New England Journal of Medicine and will be presented during the plenary session on Sunday, Dec. 8, at 2 p.m. PT at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in San Diego.

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"Over the last decade, BLINCYTO has reshaped the treatment landscape for B-ALL, offering a critical lifeline for thousands of adult and pediatric patients," said Jay Bradner, M.D., executive vice president of Research and Development and chief scientific officer at Amgen. "These powerful new data leave us little doubt about the profound impact of this medicine for a large number of children affected by this disease. We are grateful to the Children’s Oncology Group, along with the patients, families and clinical teams, for their dedication and partnership in advancing this critical study to improve the lives of children with cancer."

Based on the results of the first pre-specified interim analysis for efficacy, the study met its primary endpoint of DFS and study randomization was terminated early based on the recommendation from the data and safety monitoring committee due to the benefit observed in the BLINCYTO arm compared to the chemotherapy-only arm. Overall, the 3-year DFS was 96.0% for patients treated with chemotherapy plus BLINCYTO compared to 87.9% for those treated with only chemotherapy. The hazard ratio (HR) was 0.39 [95% confidence interval (CI) 0.24-0.64], indicating a 61% reduction in the risk of disease relapse, secondary malignant neoplasm or remission death with BLINCYTO. At 3 years, more patients remained alive and cancer free when treated with BLINCYTO plus chemotherapy compared to chemotherapy alone.

"The AALL1731 study results are truly practice-changing, further solidifying blinatumomab’s role as the standard of care for a large number of children with B-ALL," said Sumit Gupta, M.D., Ph.D., FRCPC, co-chair of the Children’s Oncology Group AALL1731 study and oncologist and clinician investigator, Division of Haematology/Oncology at The Hospital for Sick Children (SickKids) and associate professor of pediatrics at the University of Toronto. "These breakthrough data showing a significant improvement in disease-free survival are poised to bring substantial clinical value to children with newly diagnosed B-ALL."

The addition of BLINCYTO to chemotherapy in standard risk patients resulted in outcomes similar to those previously achieved in only the most favorable pediatric risk subsets. Among SR-Average patients, 3-year DFS was 97.5% for patients treated with BLINCYTO compared to 90.2% for those treated with only chemotherapy (HR 0.33, CI 0.15-0.69). For SR-High patients, 3-year DFS was 94.1% for those treated with BLINCYTO compared to 84.8% for those treated with only chemotherapy (HR 0.45, 95% CI 0.24-0.85).

"Relapsed ALL remains a major cause of pediatric cancer mortality, with nearly half of the relapses occurring in children with standard-risk B-ALL," said Rachel E. Rau, M.D., co-chair of the Children’s Oncology Group AALL1731 study, pediatric hematologist-oncologist at Seattle Children’s Hospital and associate professor of pediatrics at the University of Washington. "These findings underscore the progress made with blinatumomab in preventing relapse and support its role as a critical addition to current therapeutic strategies."

Safety results are consistent with the known safety profile of BLINCYTO. BLINCYTO has demonstrated a positive balance of benefits and risks, with only 0.3% of first courses associated with Grade 3+ cytokine release syndrome (CRS) and 0.7% with seizures. A higher risk of infections was observed in the BLINCYTO arm.

These results provide the first evidence supporting BLINCYTO for use in the consolidation phase in newly diagnosed pediatric Philadelphia chromosome-negative (Ph-) B-ALL patients. This groundbreaking first-in-class Bispecific T-cell Engager (BiTE) therapy is now backed by additional evidence reinforcing its role in redefining a standard of care for both adult and pediatric patients, starting from one month old, regardless of measurable residual disease (MRD) status. The findings further establish BLINCYTO as a versatile first-line consolidation therapy across all ages and treatment backbones.

The NCI’s Cancer Therapy Evaluation Program (CTEP), which sponsored the study will share data with the U.S. Food and Drug Administration as part of their ongoing communications relating to the trial.

On December 7, 2024 bluebird bio, Inc. (Nasdaq: BLUE) reported updated data from patients with beta-thalassemia who require regular blood transfusions treated with betibeglogene autotemcel (beti-cel, approved commercially as ZYNTEGLO) in clinical studies (Press release, bluebird bio, DEC 7, 2024, View Source [SID1234648864]). The data was presented today at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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"Updated follow-up data of up to 10 years showed that patients treated with beti-cel in clinical trials experienced durable transfusion independence and normal or near-normal hemoglobin, regardless of genotype and age, and a continued favorable safety profile", said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. "We are deeply grateful for the ongoing commitment of our investigators, patients, and study participants. Our collective efforts are not only advancing the field of gene therapy but also providing new hope and possibilities for individuals with severe genetic diseases."

"Data at ASH (Free ASH Whitepaper) demonstrate the durability of beti-cel through 10 years of long-term follow-up, giving additional confidence in that the transformational outcomes observed in parent studies are sustained over time," said Alexis Thompson, MD, MPH, Chief of the Division of Hematology at Children’s Hospital of Philadelphia, which is a Qualified Treatment Center for ZYNTEGLO. "These long-term data demonstrate beti-cel’s continued positive impact on iron management outcomes over time, which can help inform treatment decisions by clinicians who are now using this therapy in the real-world setting."

Betibeglogene Autotemcel (beti-cel) Gene Addition Therapy results in durable Hemoglobin A (HbA) Production with up to 10 Years of Follow-Up in Participants with Transfusion-Dependent β-Thalassemia (Poster #2194)

Long-term outcomes with beti-cel in adult and pediatric patients with TDT were presented in a poster session. The data focused on 63 adult and pediatric study participants who had received beti-cel in a Phase 1/2 or Phase 3 study. Two participants had 10 years of follow-up, and 51 (81.0%) participants had 5 or more years of follow-up. Additionally, iron status was assessed in study participants who achieved TI and discontinued chelation therapy. Results showed that majority of participants treated with beti-cel achieved TI. All participants achieved platelet and neutrophil engraftment. Specific findings showed:

Of 63 patients, 52 (90.2% in Phase 3 studies and 68.2% in Phase 1/2 studies) achieved TI. All except one patient maintained TI through last follow-up. The median weighted average hemoglobin during TI was 10.2 mg/dL for Phase 1/2 studies and 11.2 mg/dL for Phase 3 studies. Achievement and maintenance of TI and median weighted average hemoglobin were similar across ages and genotypes.
Study participants treated with beti-cel who achieved and maintained TI demonstrated effective restoration of iron homeostasis over time and reduced iron management burden. Among participants who achieved TI, improvements in serum ferritin and liver iron concentration were sustained through month 60. 28/37 (75.7%) study participants who achieved TI in Phase 3 studies are no longer undergoing iron chelation therapy.
Both adult and pediatric health-related quality of life scores (HRQoL) remained above the normative population mean up to 60 months. All 26 participants who achieved TI and completed a questionnaire reported an overall benefit with beti-cel.
The safety profile was consistent with known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. None of the study participants had a fatal event. No beti-cel–related serious adverse events were reported more than 2 years after infusion through last follow-up. No malignancies, insertional oncogenesis or vector-derived replication-competent lentivirus were reported in any study participants.
Beti-cel was approved by the FDA in August 2022 and is commercially available in the United States as ZYNTEGLO.

About ZYNTEGLO (betibeglogene autotemcel) or beti-cel

ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene therapy approved for the treatment of beta-thalassemia in adult and pediatric patients who require regular red blood cell transfusions. ZYNTEGLO works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem and progenitor cells to enable the production of a modified functional adult hemoglobin (HbAT87Q). Once a patient has the βA-T87Q-globin gene, they have the potential to increase ZYNTEGLO-derived adult hemoglobin (HbAT87Q) and total hemoglobin to normal or near normal levels that can eliminate the need for regular red blood cell (RBC) transfusions.

Indication

ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions.

Important Safety Information

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100.

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Risk of Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells.

Risk of Insertional Oncogenesis

There is a potential risk of LVV mediated insertional oncogenesis after treatment with ZYNTEGLO.

Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted.

In the event that a malignancy occurs, contact bluebird bio at 1 833-999-6378 for reporting and to obtain instructions on collection of samples for testing.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis.

Anti-retroviral and Hydroxyurea Use

Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed. If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.

Interference with Serology Testing

Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR‑based assay.

Adverse Reactions

The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Drug Interactions

Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates.

Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Pregnancy/Lactation

Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility. ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician.

ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration.

Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO.

Advise patients of the option to cryopreserve semen or ova before treatment if appropriate.

On December 7, 2024 Galapagos NV (Euronext & NASDAQ: GLPG) reported additional data from the ongoing Phase 1/2 ATALANTA-1 study of its CD19 CAR T-cell therapy, GLPG5101 (Press release, Galapagos, DEC 7, 2024, View Source [SID1234648899]). The results, featured in an oral presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, demonstrate an encouraging efficacy and safety profile in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). Most patients in the study received GLPG5101 as a fresh, fit, stem-like, early memory CD19 CAR T-cell therapy, with a median vein-to-vein time of seven days.

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"Shorter vein-to-vein time can lead to improved patient outcomes and remains an important unmet need in CAR-T therapy," said Marie José Kersten, MD, ATALANTA-1 Principal Investigator and Professor of Hematology at the Department of Hematology at Amsterdam University Medical Center. "I am impressed by the latest data on GLPG5101, which demonstrate a promising efficacy and safety profile. With a median vein-to-vein time of just seven days, GLPG5101 has the potential to offer speed and scheduling flexibility, comparable to off-the-shelf therapies."

"CAR-T therapies are highly personalized treatments that currently undergo a time-intensive manufacturing process taking multiple weeks to months. For many patients with rapidly progressing cancers, every day counts, and treatment delays can be detrimental," said Jeevan Shetty, MD, Head of Clinical Development Oncology at Galapagos. "We are steadfast in our commitment to bring innovation to cell therapies to address the most significant medical challenges. Our latest data at ASH (Free ASH Whitepaper) strongly support the feasibility of our innovative decentralized cell therapy manufacturing platform in delivering fresh, fit cells with a median vein-to-vein time of just seven days, driving positive patient outcomes."

The new ATALANTA-1 data are summarized below:
The ongoing ATALANTA-1 study included updated data on patients with mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). As of the April 25, 2024, data cut-off, 49 patients received CD19 CAR T-cell therapy infusion, and safety and efficacy results were available for 45 patients and 42 patients, respectively.

High objective response rates (ORR) and complete response rates (CRR) were observed in the pooled Phase 1 and Phase 2 efficacy analysis set, split by indication:
In patients with MCL, all 8 of 8 efficacy-evaluable patients responded to treatment (ORR and CRR 100%).
In patients with MZL, FL, objective and complete responses were observed in 20 of 21 efficacy-evaluable patients (ORR and CRR 95%).
In patients with DLBCL, 9 of 13 efficacy-evaluable patients responded to treatment (ORR 69%), with 7 patients achieving a complete response (CRR 54%). Of the 7 patients with DLBCL who received the higher dose, 6 responded to treatment (ORR 86%) with 5 achieving a complete response (CRR 71%).
Of the 15 minimal residual disease (MRD)-evaluable patients with a complete response, 12 patients (80%) achieved MRD negativity and remained in complete response at data cut-off.
The median study follow-up was 3.3 months for FL and DLBCL with a range of 0.9-21.2 months, and 4.4 months for MCL with a range of 1-24.4 months.
GLPG5101 showed an encouraging safety profile, with the majority of Grade ≥ 3 treatment emergent adverse events being hematological. One case of CRS Grade 3 was observed in Phase 1 and one case of ICANS Grade 3 was observed in Phase 2.
96% of patients (47 of 49) received an infusion with fresh, fit, stem-like early memory CD19 CAR T-cell therapy, with 91.5% (43 of 47) achieving a vein-to-vein time of seven days, thereby avoiding cryopreservation, and eliminating the need for bridging therapy.
Strong and consistent in vivo CAR-T expansion levels and products consisting of stem-like, early memory phenotype T cells were observed in all doses tested.
About the ATALANTA-1 study (EudraCT 2021-003272-13)

ATALANTA-1 is an ongoing Phase 1/2, open-label, multicenter study to evaluate the safety, efficacy and feasibility of decentralized manufactured GLPG5101, a CD19 CAR-T product candidate, in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). GLPG5101 is a second generation anti-CD19/4-1BB CAR-T product candidate, administered as a single fixed intravenous dose. The primary objective of the Phase 1 part of the study is to evaluate the safety and preliminary efficacy to determine the recommended dose for the Phase 2 part of the study. Secondary objectives include assessment of efficacy and feasibility of decentralized manufacturing of GLPG5101. The dose levels that were evaluated in Phase 1 are 50×106 (DL1), 110×106 (DL2) and 250×106 (DL3) CAR+ viable T cells. The primary objective of the Phase 2 part of the study is to evaluate the objective response rate (ORR), while the secondary objectives include complete response rate (CRR), duration of response, progression free survival, overall survival, safety, pharmacokinetic profile, and the feasibility of decentralized manufacturing. Each enrolled patient will be followed for 24 months.

On December 7, 2024 HanX Biopharmaceuticals reported presented poster presentations at the 2024 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting , held in San Diego, CA, USA, December 7–10 : " A Phase IB Clinical Trial INVESTIGATING the Safety, Tolerability, and Pharmacokinetics of HX009," and " A Novel BsAb Dual Targeting PD-1xCD47 in Patients with EBV+ Non-Hodgkin Lymphoma (NHL) (Press release, HanX Biopharmaceuticals, DEC 7, 2024, View Source [SID1234655963]).

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HX009 is a clinical-stage investigational anti-PD-1 and anti-CD47 bifunctional large molecule cancer immunotherapy independently developed by Hans-Eti. Two Phase I single-agent dose-escalation trials in solid tumors and one in lymphoma have been successfully completed in Australia and China. Single-agent data demonstrated favorable safety and tolerability, with single-agent anti-tumor efficacy observed in multiple indications, including lymphoma. Existing data support advancement to Phase II and combination trials. The company is currently conducting multicenter Phase II trials in multiple clinical indications. This poster presentation reported data from the ongoing Phase IB lymphoma program in the EBV+ NHL subgroup. HX009 demonstrated a favorable safety profile at a single dose of 10 mg/kg Q2W . Preliminary efficacy assessment in 14 patients with refractory/relapsed EBV+ NHL showed three partial responses and four sustained-release (SD) outcomes.

Dr. Henry Li, CEO/CSO of Hans Ait , and Dr. Zhang Lei, CMO, attended this year’s annual meeting and said, "We are very pleased to have the opportunity to report the results of this study to everyone at this annual meeting. Currently, there is no unified standard treatment for EBV+NHL. In clinical practice, the treatment of EBV+ and EBV- basically uses similar drugs with poor efficacy. In this clinical trial, we have observed that HX009 monotherapy can cause objective remission, suggesting the therapeutic potential of HX009 in this indication. We look forward to rapidly advancing this clinical trial and providing patients with new treatment options as soon as possible."

On December 6, 2024 Biomea Fusion, Inc. ("Biomea") (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing oral covalent small molecules to treat and improve the lives of patients with diabetes, obesity, and genetically defined cancers, reported that it will host a conference call and webcast on Monday, December 9, 2024 at 4:30 pm EST to present data from COVALENT-103, the company’s Phase I trial of BMF-500, an investigational covalent FLT3 inhibitor developed using the proprietary FUSION System, in adult patients with relapsed or refractory acute leukemia (Press release, Biomea Fusion, DEC 6, 2024, https://investors.biomeafusion.com/news-releases/news-release-details/biomea-fusion-host-conference-call-present-initial-clinical-data [SID1234648852]).

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Conference Call and Webcast Details
Webcast of Biomea’s investor update on Monday, December 9, 2024 at 4:30 pm EST will be available to registered attendees under the Investors and Media section of the company’s website at View Source A replay of the presentation will be archived on Biomea’s site following the event.

About COVALENT-103
COVALENT-103 is a multicenter, open-label, non-randomized trial seeking to evaluate the safety and efficacy of BMF-500, a twice daily oral treatment, in adult patients with relapsed or refractory acute leukemia with FMS-like tyrosine kinase 3 (FLT3) wild-type and FLT3 mutations. Additional information about the Phase I clinical trial of BMF-500 can be found at ClinicalTrials.gov using the identifier, NCT05918692.

About BMF-500
BMF-500, an investigational, novel, orally bioavailable, highly potent and selective covalent small molecule inhibitor of FLT3, was discovered and developed in-house at Biomea using the company’s proprietary FUSION System and has demonstrated encouraging potential based on extensive preclinical studies. The kinase inhibitory profile of BMF-500 showed high target selectivity, suggesting the potential for reduced off-target liabilities. BMF-500 was designed to have a therapeutic profile to allow for combinations with standard of care and/or novel targeted agents like icovamenib, Biomea’s investigational covalent menin inhibitor currently in clinical development for solid and liquid tumors as well as diabetes.

Previous data presented at the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting showed BMF-500’s picomolar affinity for inhibition of activating FLT3 mutations, including FLT3-ITD and various tyrosine kinase domain (TKD) mutations. BMF-500 demonstrated multi-fold higher potency and increased cytotoxicity than the commercially available non-covalent FLT3 inhibitor gilteritinib. These data also showed complete tumor regression in mouse models of FLT3-ITD acute myeloid leukemia (AML), with no tumor regrowth even after treatment cessation.

Data presented at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting exhibited the potential utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of BMF-500 and icovamenib. Additionally, Biomea has shown the potential of combinatorial approaches of BMF-500 and icovamenib with MEK and BCL2 blockade in other preclinical studies. These data provide preclinical evidence for combining pathway-specific inhibitors as a promising therapeutic strategy for further investigation in acute leukemia.

About FLT3 in AML
FLT3 is a receptor tyrosine kinase (RTK) that plays a central role in the survival, proliferation, and differentiation of immature blood cells. FLT3 gene mutations are common in patients with AML and are associated with a poor prognosis. Nearly 30% of AML patients have a FLT3 mutation, representing more than 7,000 incident patients in the U.S. each year. In addition, academic literature suggests that more than 50% of AML patients with an NPM1 mutation also harbor a FLT3 mutation. While FLT3-specific and pan-tyrosine kinase inhibitors are approved by the FDA across various lines of therapy in AML, these agents have produced relatively low rates of durable responses and overall survival remains an unmet need.