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Postdoctoral research fellow at Brigham and Women's Hospital

The postdoctoral research fellow at Brigham and Women's Hospital discussed research on focused ultrasound aimed at enhancing AAV delivery across the blood-brain barrier.

Bernie Owusu-Yaw, PhD, on Focused Ultrasound Mediated Delivery for AAV Gene Therapy

Patient use of the 2 FDA-approved gene therapy products for sickle cell disease (SCD), Vertex Pharmaceuticals' and CRISPR Therapeutics’ 

 (exa-cel; marketed as Casgevy) and bluebird bio’s 

 (lovo-cel; marketed as Lyfgenia), in the commercial setting has remained low.

Despite the approval of both gene therapy products by the FDA occurring simultaneously on December 8, 2023, only 4 patients have begun treatment with lovo-cel in the commercial setting, while 20 patients are reported to have begun treatment with exa-cel. Alongside the number for lovo-cel, bluebird also pointed out that this year 4 patients have started on elivaldogene autotemcel (Lenti-D, Skysona), its marketed gene therapy for cerebral adrenoleukodystrophy, and 19 patients have started on betibeglogene autotemcel (beti-cel, Zynteglo), its marketed gene therapy for transfusion dependent thalassemia (TDT). As such, bluebird bio has reported 23 total cell collections for SCD/TDT gene therapies lovo-cel and beti-cel. The company expects that patient uptake of the 3 aforementioned therapies will continue to increase, with 85 patient starts expected across the therapies by the end of the year.

“We are seeing clear evidence that our commercial launch is accelerating, with over 20 cell collections completed in SCD and TDT to date in 2024, and more than 40 additional patients already scheduled to initiate the treatment journey for a bluebird gene therapy by the end of this year,” Andrew Obenshain, MBA, the chief executive officer of bluebird bio, said in a statement.

 “We are further encouraged by the commitment to provide patient access across both commercial and government payers, most recently conveyed through multiple positive Medicaid decisions and the growing number of published coverage policies for Lyfgenia, and we expect approximately 85 patient starts across our portfolio this year.”

Notably, unlike lovo-cel, exa-cel is indicated for both SCD and TDT. Since Vertex has not clarified the breakdown of patients treated with exa-cel for each disease, direct comparison is difficult. The approval in TDT came slightly later, with 

“Vertex delivered another strong quarter of revenue growth coupled with outstanding execution across the business, and we are increasing our full year product revenue guidance,” Reshma Kewalramani, MD, the chief executive officer and president of Vertex, said in an August 1, 2024, statement.

 “Our focus for the second half of the year remains on commercial execution in cystic fibrosis and the global launch of Casgevy, readying for the upcoming potential launches of the vanzacaftor triple in cystic fibrosis and suzetrigine in acute pain, while rapidly advancing a robust pipeline that is poised to deliver value for patients and shareholders for the long term.”

Beyond gene therapy for SCD and TDT, uptake of 

hemophilia gene therapies has also been slow

. Although BioMarin’s valoctocogene roxaparvovec (val-rox, marketed as Roctavian) was approved in June 2023, the first patient outside of clinical trials 

 until December 2023, at the Center for Inherited Bleeding Disorders (CIBD) in California.

 Just this month, BioMarin announced that 

 with regard to val-rox, with the company now mainly focusing on distributing the gene therapy in the United States, Germany, and Italy, the 3 countries in which it has been approved for use by relevant regulatory authorities and is reimbursed.

 UniQure and CSL Behring’s hemophilia B gene therapy, etranacogene dezaparvovec (marketed as Hemgenix), which was 

, has also been slow to be embraced by patients.

“We haven't seen a lot of patients dosed yet,” Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, told 

 regarding Hemegenix earlier in 2024. “And I don't think that’s related to either the enthusiasm of the clinicians or the patients, but really just the mechanics of how to deliver this in the clinical space, as opposed to the research trials... We've seen that a lot of the hemophilia treatment center sites have got their components together, their infrastructure and personnel so that they can actually start delivering this in the commercial setting. And so, I'm really looking forward to seeing this making a difference in patients' lives in a real world setting.”

REFERENCES
1. bluebird bio reports second quarter 2024 results and highlights operational progress and 2024 guidance. News release. bluebird bio, Inc. August 14, 2024. Accessed August 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-second-quarter-2024-results-and-highlights
2. Stock dive for bluebird as sickle cell gene therapy lags behind Vertex rival. News article. Anna Bratulic. FirstWord Pharma. August 14, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5885598
3. Vertex announces US FDA approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Incorporated. January 16, 2024. Accessed August 15, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
4. Vertex reports second quarter 2024 financial results. News release. Vertex Pharmaceuticals Incorporated. August 1, 2024. Accessed August 15, 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-second-quarter-2024-financial-results
5. Center for Inherited Blood Disorders Administers Country's First Gene Therapy Infusion to Treat Hemophilia A. News release. Center for Inherited Blood Disorders. January 11, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5817834?from=article
6. BioMarin Announces Updated Strategy for ROCTAVIAN® to Focus on U.S., Germany and Ital. News release. BioMarin Pharmaceutical Inc. August 5, 2024. Accessed August 15, 2024. https://investors.biomarin.com/news/news-details/2024/BioMarin-Announces-Updated-Strategy-for-ROCTAVIAN-to-Focus-on-U.S.-Germany-and-Italy/default.aspx
7. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. Accessed August 15, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

bluebird bio has reported 23 total cell collections for SCD and TDT gene therapies lovo-cel and beti-cel and Vertex Pharmaceuticals has reported approximately 20 cell collections for SCD/TDT gene therapy exa-cel.

Topic

Uptake of Nononcology Gene Therapy Remains Slow in Hematology

(arsa-cel, OTL-200; Orchard Therapeutics) is a gene-edited cell therapy designed to restore arylsulfatase A (ARSA) enzyme activity in children with presymptomatic (PS) late infantile (LI), PS early juvenile (EJ), or early symptomatic (ES) early juvenile (EJ) metachromatic leukodystrophy (MLD).

 arsa-cel under the name Lenmeldy to become the first gene therapy for children with MLD to be approved in the United States, following its approval in the European Union, UK, Iceland, Switzerland, Liechtenstein and Norway under the name Libmeldy.1 Orchard Therapeutics previously announced that the FDA had accepted the biologics license application with 

The FDA’s decision was based on data from patients treated with arsa-cel across 2 clinical trials (NCT01560182; NCT03392987) and additional patients treated in expanded access frameworks. These patients had follow-up times ranging from 0.64 years to 12.19 years (median, 6.76).

“Metachromatic leukodystrophy, is a really important unmet need in the pediatric community. So, this is a disease that's rare, it affects about one in 40,000 children. And up until recently, we have had no curative treatment option for this,” Madeleine Powys, MBBS, Staff Specialist, Blood Transplant and Cell Therapies, The Children's Hospital at Westmead, told 

. "Autologous hematopoietic stem cell gene therapy has offered really promising new hope for these patients.”

Madeleine Powys, MBBS, on Lessons Learned With Libmeldy

Arsa-cel is currently being evaluated in 6 participants enrolled in a phase 3 clinical trial (NCT04283227). The trial enrolled participants with documented biochemical and molecular diagnosis of MLD, including low ARSA activity and identification of 2 disease-causing ARSA alleles, with novel mutations analyzed and excluded as common polymorphisms, alongside specific genotype criteria. Symptomatic individuals must have onset between 7 and 17 years of age, or pre-symptomatic participants must be less than 17 years at treatment initiation and have a sibling with late-juvenile MLD variant, along with normal cognitive and motor function, with seizures or disease signs revealed by instrumental evaluations not being exclusionary if present alone, and compliance with contraceptive use requirements if applicable, with signed informed consent or assent provided by the participant or guardian.

The exclusion criteria for the study include documented HIV infection, malignant neoplasia except localized skin cancer or hereditary cancer syndrome unless successfully treated with no recurrence, myelodysplasia, acute myeloid leukemia, or serious hematological disorders, current enrollment in other interventional trials, prior allogeneic HSPC gene therapy or gene therapy, symptomatic herpes zoster unresponsive to treatment, active tuberculosis unless on antibiotic prophylaxis, acute or chronic stable Hepatitis B or positive Hepatitis C RNA test result unless specific conditions are met, end-organ dysfunction, severe infection not responsive to treatment, or other severe diseases deemed inappropriate for the study by the investigator. Additionally, testing for other transmissible infectious agents may be considered, and participants with elevated liver enzymes or bilirubin may be included after discussion and agreement with the medical monitor.

The study’s primary measures involve assessing the OTpbmsL-200 Arylsulfatase A (ARSA) activity levels in cerebrospinal fluid (CSF) and the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter brain regions, both evaluated at 24 months post-treatment, with changes from baseline being monitored.

Secondary measures involve evaluating changes in ARSA activity levels in CSF and neuronal metabolite ratio in white matter brain regions, assessing ARSA levels in peripheral blood mononuclear cells (PBMCs) and specific subtypes, comparing neuronal metabolite ratios to baseline, siblings, or untreated controls, determining engraftment through lentiviral positivity in bone marrow progenitors and vector copy number in BM cells and PBMCs, assessing severity scale for brain MRI, neurocognitive function, full neurological clinical examination, gross motor function classification, nerve conduction velocity, Vineland Adaptive Behavior Scale, and monitoring conditioning regimen and non-conditioning-related adverse events up to 8 years post gene therapy, along with hematological reconstitution, infusion-related reactions, immune response, abnormal clonal proliferation, replication-competent lentivirus, and integration site analysis findings over time.

, held February 4-9, in San Diego, California, by Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy. The data were from 5 patients with LJ MLD that had follow-up ranging from 3.2 to 21.3 months (median, 17.3). At the time of treatment, 3 patients had PS MLD and 2 had ES MLD. The group included a 2.7-year-old girl (PS), a 9.9-year-old boy (ES), a 15.2-year-old boy (PS), a 6.6-year-old girl (PS), and 10.9-year-old boy (ES) as of the December 2023 cutoff date.

"This represents of course, the proof of principle that gene therapy with ex- vivo lentiviral gene therapy into stem cells can correct a lysosomal storage disorder (LSD)... and could be applicable to other LSDS. So we're working on new diseases to bring this approach of enzyme correction also to other LSDs," investigator Alessandro Aiuti, MD, PhD, deputy director, clinical research, and head, Clinical Research Unit, San Raffaele Telethon Institute for gene therapy, and Group leader, Pathogenesis and therapy, primary immunodeficiencies unit, and full professor, Università Vita Salute San Raffaele, and chief of clinic, Pediatric Immunohematology Unit, San Raffaele, told 

Data from these participants showed that they all had normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings. Time to neutrophil engraftment ranged from 26 to 42 days (median, 33) posttreatment and time to platelet engraftment ranged from 25 to 46 days (median, 26) posttreatment. ARSA activity reached supranormal levels in the PBMCs and in CD15+ cells and increased to normal levels in the CSF in 3 patients for whom central nervous system pharmacodynamic efficacy measures were available.At 90 days after administration of arsa-cel transduced bone marrow progenitors made up between 23.81% to 81.25% of bone marrow progenitors. At this time point, the PBMCs showed a median vector copy number (VCN) of 0.49 copies/cell and the CD15+ cells showed a median VCN of 0.82 copies/cell.

In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel. One nonserious AE deemed potentially related to the therapy, a case of erythematous rash, occurred in 1 patient. No SAEs deemed potentially related to the Busulfan conditioning regimen occurred; although cases of febrile neutropenia, cytopenia, and stomatitis were deemed to have potential relation to the regimen. An SAE of upper respiratory tract infection occurred in 1 patient. One patient with prolonged thrombocytopenia who had previously experienced treatment-failure with allogeneic transplant in the form of autologous reconstitution was administered thrombopoietin receptor agonist therapy for 5 months. No multilineage engraftment of transduced cells or malignancy occurred and there was no indication of clonal expansion or replication competent lentivirus.

1. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph
2. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed September 18, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
3. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsageneautotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #92
4. Gallo V, Calbi V, De Mattia F, et al. Lentiviral hematopoietic stem cell gene therapy (atidarsageneautotemcel) for late juvenile metachromatic leukodystrophy (MLD). Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #96

The gene-edited cell therapy has been approved as Lenmeldy by the FDA. 

Phase 3 Trial Seeks to Continue Supporting Arsa-Cel Gene Therapy for MLD 

The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has provided Ocugen with a positive opinion regarding the use of data from the United States–based phase 2/3 GARDian3 clinical trial (NCT05956626) to support a marketing authorization application (MAA) for OCU410ST, an investigational adeno-associated virus (AAV) vector-based gene therapy, for the treatment of Stargardt disease.

The EMA’s decision was based on data from the phase 1 GARDian clinical trial (NCT05956626), in which evaluable treated eyes showed 48% slower lesion growth compared with untreated eyes at 12 months of follow-up. In addition, evaluable treated eyes showed improvement in best-corrected visual acuity (BCVA) of almost 2 lines or 9 letters compared with untreated eyes, a changed deemed clinically meaningful and statistically significant (

“This positive opinion endorses a single trial as the basis for both biologics license application [BLA] and MAA submissions and brings us closer to providing a 1-time, modifier gene therapy to approximately 100,000 Stargardt patients in the United States and Europe combined,” Shankar Musunuri, PhD, the chairman, chief executive officer, and cofounder of Ocugen, said in a statement.

 “We are very encouraged about the prospect of addressing the unmet medical need that exists for these patients who currently have no approved treatment options available to them.”

 The phase 2/3 trial will enroll 51 participants with Stargardt disease, and 34 of the patients will be treated with a 1-time subretinal injection of OCU410ST (200 μL at a concentration of 1.5 × 10¹¹ vector genomes/mL) in their worse-seeing eye, whereas 17 participants will act as untreated controls. The study’s primary end point is reduction in atrophic lesion size, with major secondary end points including improvements in BCVA and low-luminance visual acuity compared with controls.

 In addition, GARDian3 will feature a masked interim analysis of 16 of the treated patients and 8 of the control group patients at the 8-month time point.

“Initiating dosing in this pivotal phase 2/3 study is an important advancement for Ocugen and more importantly for the Stargardt community,” Huma Qamar, MD, MPH, chief medical officer of Ocugen, said in a statement at the time the first patient’s dosing was announced.

 “The adaptive design of this trial, including a masked interim analysis at 8 months on 24 subjects, enables us to efficiently evaluate early signals of efficacy and safety while optimizing study conduct.”

Notably, 1-year follow-up data from GARDian3 will be used to support both the planned BLA submission to the FDA and the planned MAA submission to the EMA.

 Ocugen anticipates that GARDian3 will finish enrolling patients in the first quarter of next year and expects to file a BLA with the FDA in the first half of 2027.

was granted rare pediatric disease designation

 (RPDD) from the FDA for the treatment of ABCA4-associated retinopathies, including Stargardt disease, retinitis pigmentosa 19, and cone-rod dystrophy 3.

 OCU410ST has previously been granted orphan drug designations for ABCA4-associated retinopathies by both the FDA and EMA.

“This latest designation for OCU410ST reaffirms the urgency of providing a therapeutic option to Stargardt patients who have no FDA-approved treatment available,” Musunuri said in a statement at the time of the RPDD designation announcement.

 “This inherited retinal disease presents itself most often in childhood—making Stargardt disease a diagnosis that not only affects the patient but impacts the entire family.”

REFERENCES
1. Ocugen, Inc. announces positive scientific advice from the European Medicines Agency related to the approval pathway for OCU410ST—modifier gene therapy for Stargardt disease. News release. Ocugen Inc. August 13, 2025. Accessed August 14, 2025. https://ir.ocugen.com/news-releases/news-release-details/ocugen-inc-announces-positive-scientific-advice-european-0
2. Ocugen, Inc. announces first patient dosed in phase 2/3 GARDian3 pivotal confirmatory trial for OCU410st—novel modifier gene therapy candidate for Stargardt disease. News release. July 18, 2025. Accessed August 14, 2025. https://ir.ocugen.com/news-releases/news-release-details/ocugen-inc-announces-first-patient-dosed-phase-23-gardian3
3. Ocugen announces rare pediatric disease designation granted for OCU410ST—modifier gene therapy for the treatment of Stargardt disease. News release. Ocugen Inc. May 27, 2025. Accessed August 14, 2025. https://ir.ocugen.com/news-releases/news-release-details/ocugen-announces-rare-pediatric-disease-designation-granted

Notably, the first patient was dosed in the GARDian3 in July 2025.

EMA's CHMP Gives Ocugen the Green Light to Submit MAA for OCU410ST Based on GARDian3 Trial

Galapagos' GLPG5101, an investigational CD19-directed chimeric antigen receptor (CAR) T-cell therapy product, has received regenerative medicine advanced therapy (RMAT) designation from the FDA for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL).

The RMAT designation was granted based on data from patients with R/R B-cell non-Hodgkin lymphoma treated in the phase 1/2 ATALANTA-1 clinical trial (NCT06561425), which includes a subset of patients with R/R MCL. According to Galapagos, among the findings were “high objective and high complete response rates.” The safety profile was characterized as “manageable”, with rates of high-grade cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome being low. The company also stated that rates of participants dropping out of the trial were also low.

“This designation reflects the promising clinical activity and safety profile observed in our ongoing phase 1/2 study and supports our commitment to delivering an effective and timely treatment option to patients in need,” Omotayo Fasan, MRCP, DTM&H, MBBS, the head of the clinical development program at Galapagos, said in a statement.

 “With RMAT status allowing for closer collaboration with the FDA, this will enable additional opportunities for accelerated development and assessment timelines.”

Alongside the announcement of the RMAT designation, Galapagos noted that it plans to present updated data from the ongoing ATALANTA-1 trial at an unspecified future medical conference. Notably, the ATALANTA-1 trial is evaluating the feasibility and efficacy of decentralized manufacturing for GLPG5101, which is given intravenously in a single fixed dose, as a secondary objective. The study includes eligibility for 8 hematologic malignancies.

Earlier this year, Galapagos presented data from ATALANTA-1 at 

the European Hematology Association (EHA) 2025 Congress

, held June 12 to 15, both virtually and in Milan, Italy. 

 during the conference to learn more about some of the key findings presented.

Fasan highlighted that the vein-to-vein time for GLPG5101 was short, with about 9 in 10 patients receiving their infusion in the 7-day window following leukapheresis, thus not necessitating bridging therapy. For reference, he pointed out that currently available CAR T-cell products typically have a vein-to-vein time of 4 to 6 weeks. He also noted that fresh CAR T-cell product was given to 95% of the treated patients, stating that fresh CAR T-cell product circumvents the need for cryopreservation and is associated with benefits such as reduced toxicity and good expansion.

“This therapy is manufactured using Galapagos’ innovative decentralized platform, which enables delivery of fresh, stemlike early memory T-cells in a median vein-to-vein time of just 7 days...” Fasan told 

. “Galapagos’ EHA results suggest a meaningful advance in CAR [T-cell] therapy delivery and safety. The decentralized, 7-day manufacturing approach demonstrates that fresh, early memory CAR T cells can be reliably delivered in a decentralized manner, enhancing physician confidence and expanding treatment access—especially for patients too fragile to wait weeks for traditional CAR-T production.”

Notably, Galapagos is also tracking long-term follow-up of patients treated with GLPG5101 and several of its other CAR T-cell products through its phase 3 HESPERIA long-term follow-up study (NCT06652633).

 series. The study is assessing the long-term safety and efficacy of patients treated with Galapagos CAR T-cell products over 15 years post treatment. According to the company’s pipeline page on its own website, Galapagos CAR T-cell products include GLPG5101, which is being evaluated in ATALANTA-1; GLPG5201, which is being evaluated in the phase 1/2 EUPLAGIA-1 clinical trial (CTIS: 2022-501686-47-00); and GLPG5301, which is being evaluated in the phase 1/2 PAPILIO-1 clinical trial (EU CT 2022-500782-27-00).

REFERENCES
1. Galapagos NV announces U.S. FDA regenerative medicine advanced therapy (RMAT) designation granted to GLPG5101 for the treatment of relapsed/refractory mantle cell lymphoma. News release. August 6, 2025. Accessed August 13, 2025. https://www.glpg.com/press-releases/galapagos-nv-announces-u-s-fda-regenerative-medicine-advanced-therapy-rmat-designation-granted-to-glpg5101-for-the-treatment-of-relapsed-refractory-mantle-cell-lymphoma/
2. Our pipeline. Galapagos NV. February 13, 2025. Accessed August 13, 2025. https://www.glpg.com/innovation/pipeline/

The RMAT designation was granted based on data from the phase 1/2 ATALANTA-1 clinical trial, which includes a subset of patients with R/R MCL.

Galapagos Snags FDA RMAT Designation for R/R Mantle Cell Lymphoma CAR T-Cell Therapy

The FDA is requiring updated labeling for bluebird bio's elivaldogene autotemcel (eli-cel; Skysona), a gene therapy product comp of engineered autologous CD34+ hematopoietic stem cells intended to treat early, active cerebral adrenoleukodystrophy (CALD), to reflect an increased risk of hematologic malignancy following treatment with the product.

Specifically, the agency is requiring updates to the Boxed Warning, Indications and Usage, Warnings and Precautions, and Adverse Reactions – Clinical Trials Experience sections of eli-cel's prescribing information and Medication Guide. With regard to the revised Indications and Usage section, only patients without an available human leukocyte antigen (HLA)–matched donor for allogeneic hematopoietic stem cell (allo-HSC) are eligible to receive eli-cel.

“...Skysona should only be used in CALD patients without suitable alternative treatment options, given the increased risk of hematologic malignancy,” the FDA said in a press release announcing the required labeling changes.

 “The Limitations of Use section retains language emphasizing careful consideration of appropriateness and timing of treatment.”

The changes are to be made in relation to new safety information regarding the risk of hematologic malignancies that has become available following a probe by the FDA 

 The FDA stated that as of July 2025, 10 of 67 patients (15%) treated in clinical trials for eli-cel have developed hematologic malignancies.

 in September 2022, only 3 of the 67 patients (4%) had developed known hematologic malignancies.

“Current reports suggest that the time to diagnosis of hematologic malignancy ranges from 14 months to 10 years after Skysona administration,” the FDA also stated.

 “Nine of the 10 patients have been treated with allo-HSCT (with or without chemotherapy) for the hematologic malignancy. The malignancies are life-threatening conditions, and 1 death related to treatment for malignancy has occurred. One patient developed recurrence of myelodysplastic syndrome (MDS) after initial treatment, which required retreatment. Importantly, some patients developed malignancy before Skysona had time to potentially provide therapeutic benefit for their CALD.”

 in October 2024, the aforementioned patient who died had received allo-HSCT for the treatment of their MDS.

 The patient’s death, which occurred 20 months after receiving the allo-HSCT, was attributed to presumed graft-vs-host disease (GVHD). At the time of the paper’s writing, only 7 of the 67 patients had been diagnosed with hematologic malignancies. The 67 patients were treated across the phase 2/3 ALD-102 (NCT01896102), phase 2/3 ALD-104 (NCT03852498), and LTF-304 (NCT02698579) clinical trials, with LTF-304 being an ongoing long-term follow-up study for patients treated in ALD-102 and ALD-104.

"The risk of oncogenesis with eli-cel must be weighed against the severity and natural history of CALD as well as the availability of other treatments and their risks, including allogeneic HSCT,” first author Christine N. Duncan, MD, the medical director of clinical research and clinical development for the Gene Therapy Program at Boston Children’s Hospital, and colleagues, wrote in the paper.

 “Overall survival was 77.8% among patients who had undergone allogeneic HSCT 4 years previously in a matched cohort study; the cumulative incidence estimate for acute grade 2 to 4 GVHD was 11.1%, and the estimate for GVHD overall was 17.2%. Moreover, the availability of HLA highly matched donors is limited and is a crucial determinant of outcomes in patients undergoing allogeneic HSCT. Most patients who received eli-cel in the ALD-102 and ALD-104 studies benefited clinically, with 81% four-year survival free of major functional disabilities and hematologic cancer, and without referral for allogeneic HSCT. Therefore, the probability and magnitude of benefit that gene therapy can offer in patients who do not have an appropriate donor must be considered. Because gene therapy is an evolving field, ongoing follow-up is critical to understanding the longer-term safety and efficacy of novel treatments like eli-cel.”

REFERENCES
1. FDA approves required labeling changes for increased risk of hematologic malignancy following treatment with Skysona (elivaldogene autotemcel). News release. FDA. August 7, 2025. Accessed August 11, 2025. https://www.fda.gov/vaccines-blood-biologics/fda-approves-required-labeling-changes-increased-risk-hematologic-malignancy-following-treatment
2. FDA investigating serious risk of hematologic malignancy following Skysona (elivaldogene autotemcel). News release. FDA. November 27, 2025. Accessed August 11, 2025.https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-hematologic-malignancy-following-skysona-elivaldogene-autotemcel
3. Duncan CN, Bledsoe JR, Grzywacz B, et al. Hematologic cancer after gene therapy for cerebral adrenoleukodystrophy. 

. 2024;391(14):1287-1301. doi: 10.1056/NEJMoa2405541

The move was based on updated safety data from an FDA probe into the risk of hematologic malignancies in patients treated with eli-cel.

FDA Updates Labeling for bluebird's Active Cerebral Adrenoleukodystrophy Gene Therapy Eli-Cel to Reflect Risk of Hematologic Malignancy

This interview originally appeared on our sister site,

, recently interviewed Kathleen A. Dorritie, MD, a hematologist/oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania, about the current landscape of care for hematologic malignancies, a field that has seen a number of novel treatments and therapeutics introduced during the past 5 years. Dorritie noted that BTK inhibitors in chronic lymphocytic leukemia (CLL), menin inhibitors in acute myeloid leukemia (AML), and chemeric antigen receptor (CAR) T-cell therapies in multiple myeloma are among the new strategies.

“Now that we have CAR T-cell therapy in lymphoma and myeloma, we [wonder] what the next [big] thing will be,” Dorritie told 

 after a State of the Science Summit™ on hematologic malignancies that she chaired. “It's [also] very exciting to have bispecific antibodies that are FDA approved. It's exciting for patients—and for a physician treating these patients—to have so many options that have completely shifted how we approach these diseases and talk to patients in the last 5 years.”

about major updates from the National Comprehensive Cancer Network (NCCN) for the use of BTK inhibitor–based regimens in CLL, ongoing studies in leukemia that have yielded important data, and the introduction in earlier lines of multiple myeloma of quadruplet and CAR T-cell therapies.

Dorritie also drew attention to a clinical case scenario with regard to treatment strategies for a patient with newly diagnosed CLL in 

 What are some of the key updates to the NCCN guidelines regarding the use of BTK inhibitor–based regimens for treatment-naive CLL?

 Key updates include the incorporation of targeted therapies in the frontline setting. Now we have different studies showing different options than that frontline setting, even in patients who have high-risk disease with, for example, 

 mutations. The guidelines have all been updated to include either a venetoclax-based regimen up front as fixed-duration therapy or a BTK inhibitor therapy up front as a preferred line of therapy vs prior standards of care [SOC], which incorporated chemotherapy.

What updates on BTK inhibition in relapsed/refractory CLL were reported at this year’s ASCO Annual Meeting?

We’d previously seen earlier data with pirtobrutinib [Jaypirca]. [Pirtobrutinib] is the only noncovalent, reversible BTK inhibitor for patients who have received prior BTK inhibitors, such as acalabrutinib [Calquence], ibrutinib [Imbruvica], or zanubrutinib [Brukinsa], particularly patients who experienced BTK inhibitor resistance. Pirtobrutinib is a great option for them, as described in the [phase 1/2] BRUIN study [NCT03740529].

] for lisocabtagene maraleucel [liso-cel; Breyanzi] in CLL, which was 

. However, more real-world data [with this agent] were presented at ASCO, which is very interesting. [The real-world study] compared liso-cel with some SOC chemotherapies. Both progression-free survival [PFS] and overall survival were improved in the liso-cel arm compared with the SOC arm. [These results further] stress that CAR T-cell therapy is now a [viable] option in CLL. This is a newer option for patients, although it is important to get the word out to community physicians that patients do better with CAR T-cell therapy and that they should be referred to tertiary centers.

What are some ongoing studies of note in the leukemia landscape?

The 2 abstracts that caught my attention were describing the FDA-approved menin inhibitor revumenib [Revuforj]. The first [abstract] was the [phase 1/2] AUGMENT-101 study [NCT04065399]. This was a study in relapsed/refractory, 

-rearranged AML, and in these patients, the overall response rates [ORRs] in the relapsed/refractory setting were upward of 63.2%, which was very high compared with some of our other SOC [agents].

A different [phase 1/2] study [NCT03013998] [evaluated newly diagnosed patients with] 

-rearranged disease. That study combined revumenib with azacitidine [Vidaza] plus venetoclax [Venclexta], which has kind of become a standard, especially in less fit patients. The ORR in this study was 88.4% with a complete response [CR] and complete response without hematologic recovery [CRi] of 81.4%. [In] the [phase 3] VIALE-A trial [NCT02993523], [whose findings] led to the incorporation of azacitadine/venetoclax in the frontline setting, we saw CR/CRi rates of approximately 68%. This is showing that the addition of the revumenib [to standard azacitidine plus venetoclax] went on to improve outcomes. We have seen lots of advances in lymphoid malignancy and multiple myeloma, so it was exciting to have some new data in AML as well.

How have triplet and quadruplet regimens helped move the needle forward in multiple myeloma?

Triplet regimens have been the SOC for quite some time. We've had an overwhelming amount of new data coming out, initially in the transplant-eligible setting. [This includes] studies like [the phase 2] GRIFFIN trial [NCT02874742] and [the phase 3] PERSEUS trial [NCT03710603], which showed outcomes of quadruplet therapy vs a triplet regimen in [both] of the studies. In some ways, it's even more interesting for the population of patients who are considered transplant ineligible or transplant deferred, for whom we had data come out from [the phase 3] IMROZ [NCT03319667], CEPHEUS [NCT03652064], and BENEFIT [NCT04751877] trials showing that any patient who can tolerate a quadruplet regimen should be offered it. We can improve ORR and rates of minimal residual disease negativity [with this approach], which translate into PFS benefits. The overall takeaway is that we should consider quadruplet regimens for all, and in patients who can't use a quadruplet, [we can] certainly [use] a triplet regimen. It's very rare that we would recommend a doublet as a SOC option anymore.

With the FDA’s decision to approve cilta-cel and ide-cel in earlier lines of therapy for multiple myeloma, how could the continued development of CAR T-cell therapies affect treatment sequencing?

We can now use CAR T-cell therapy in the second-line setting. The bigger question has been whether we should use CAR T-cell therapy in the second-line setting, given the possible toxicities associated with it. There are certain patients for whom we do consider using CAR T-cell therapy in the second-line setting, namely ultrahigh-risk patients who do not respond for a long period after initial therapy and relapse within a year. For patients with high-risk disease, we might consider using that in the second-line setting. It does raise the question: What do we do later on? The development of CAR T-cell therapies targeting different antigens, such as GPRC5D, for which we have an FDA-approved bispecific antibody [talquetamab (Talvey)], will be needed.

For now, it's great that we have CAR T-cell therapy as an option in the second line. [In clinical practice], not many of us are using it quite yet in the second line; we may [utilize them] in the third-line setting, just because we have so many great myeloma drugs. With the quadruplet regimens, our remissions are lasting longer and longer. We have other options that we usually try to exhaust before heading to a CAR T-cell therapy, just because of toxicity concerns.

This transcript has been edited for clarity.

The hematologist/oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania discussed updates to NCCN guidelines and research to pay attention to in hematologic malignancies.




Bernie Owusu-Yaw, PhD

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