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Authors

Pediatric neurologist at the Children's Hospital of Philadelphia

John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia, discussed several still-investigational drugs and therapies for DMD.

Potential Upcoming Treatments for Duchenne Muscular Dystrophy

John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia, discussed the complicated choice doctors, patients, and families now face with a wide range of treatment options available.

Navigating the New Landscape of Care for DMD

John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia, discussed how Sarepta’s Elevidys has affected the landscape of care for DMD.


Balancing Risks and Rewards With Muscular Dystrophy Gene Therapy

The pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia discussed several still-investigational drugs and therapies for DMD.

John Brandsema, MD, on Potential Upcoming Treatments for Duchenne Muscular Dystrophy

The pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia discussed the complicated choice doctors, patients, and families now face with a wide range of treatment options available.

John Brandsema, MD, on Navigating the New Landscape of Care for DMD

The pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia discussed how Sarepta’s Elevidys has affected the landscape of care for DMD.

John Brandsema, MD, on Balancing Risks and Rewards With Muscular Dystrophy Gene Therapy

John Brandsema, MD, discusses gene transfer for the management of SMA and the recent approval of onasemnogene abeparvovec-xioi.

The Potential of Gene Transfer Therapy in SMA

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 

This interview originally appeared on our sister site,

The head of the Referral Center for Sickle Cell Disease and Clinical Research Department at Hôpital Intercommunal de Créteil of the Université Paris Cité discussed the Drepagreffe-1 and 2 studies and improvements seen over 10 years of follow-up.

Françoise Bernaudin, MD, on alloSCT Superiority Over SOC for Sickle Cell Anemia

“It's important we have demonstrated that SCT does better than chronic transfusion and better than hydroxyurea, for the outcome of stenosis, to prevent SCI, and to give a better quality of life and higher cognitive performance."

In the DREPAGREFFE-2 clinical trial (NCT05053932) allogeneic stem cell transplantation (allo-SCT) showed improvements over standard of care (SOC) in silent cerebral infarct (SCI) incidence and social quality of life (QoL), working memory, and processing speed for patients with sickle cell anemia (SCA), over 10 years of follow-up. Françoise Bernaudin, MD, the head of the Referral Center for Sickle Cell Disease and Clinical Research Department at Hôpital Intercommunal de Créteil of the Université Paris Cité, recently presented these results at the

 66th American Society of Hematology (ASH) Annual Meeting and Exposition

, held December 7-10, 2024, in San Diego, California. At the conference, 

The original prospective DREPAGREFFE-1 trial (NCT01340404) showed modest improvements between allo-SCT and SOC arms, many of which have become significant over 10 years of follow-up. Notably, Bernaudin and colleagues found that on MRI and MRA, of the 31 SOC group patients, 11 had reported SCIs—an increase of 5 incidences from 6 at enrollment—while there were no additional instances in the 28 patients in the allo-SCT group, which had 12 at enrollment. SCI were either no more visible or under 3 mm in 1 patient in the standard of care group and 4 in the allo-SCT group (

 = .010). Processing speed index (PSI) was higher for the allo-SCT group at 96.5 (SD, 21.9) compared with the standard of care group at 83.7 (SD, 14.4), which was significant (

 = .035), as well as social functioning QoL (allo-SCT: 93.8 [SD, 10.7]; standard of care: 86.4 [SD, 12.9]; 

REFERENCE
Bernaudin F, Verlhac S, Ducros-Miralles E, et al. Outcome of Cerebral Vasculopathy and Cognitive Performances 10 Years Post-Enrollment in the Drepagreffe Trial Comparing Allogeneic Stem Cell Transplantation to Standard-Care in Children with Sickle Cell Anemia and History of Abnormal Cerebral Velocities. Presented at: ASH 2024 Annual Meeting. December 7-10, 2024; San Diego, CA. Abstract LBA-5

The head of the Referral Center for Sickle Cell Disease and Clinical Research Department at Hôpital Intercommunal de Créteil of the Université Paris Cité discussed the Drepagreffe-1 and 2 studies and improvements seen over 10 years of follow-up.



Videos

The tandem CD20/CD19 targeted non-cryopreserved CAR T-cell therapy zamtocabtagene autoleucel (zamto-cel) showed promising early complete response (CR) rates and survival outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to interim findings from the pivotal phase 2 DALY II USA study (NCT04792489) presented at 

the 66th American Society of Hematology (ASH) Annual Meeting

, held December 7-10, 2024, in San Diego, California.

In the preplanned interim findings from phase 2 study, the overall response rate (ORR) was 72.8% and the complete remission (CR) rate was 50.8%. The median duration of response was 11.4 months for those with an ORR and was not yet reached for those with a CR. The median progression-free survival (PFS) was 9.0 months and the PFS rate was 55% (95% CI, 41%-67%). The median overall survival was not reached at the interim analysis.

"We are excited to share a unique platform with our tandem cell therapy. This is the first tandem CD20/CD19 CAR T-cell product delivered as a fresh infusion," 

, Division of Hematology & Oncology, Medical College of Wisconsin. "This is a preplanned analysis and there are more patients to be enrolled. We are looking forward to sharing the final results."

Zamto-cel utilizes a 4-1BB co-stimulatory domain with dual targeting domains for CD19 and CD20. The manufacturing process uses CliniMACS Prodigy at the point of care and includes apheresis, T cell separation, activation, transduction, and then expansion. After this point, the cells are infused without the need for cryopreservation. The vein-to-vein time was 12 to 14 days.

Tabelecleucel Efficacy Sustained in EBV-positive PTLD, as FDA Considers Application

"There is no cryopreservation indicated for this product, it allows for a true vein-to-vein time of 14 days," said Shah. "This platform really allows rapid delivery. You don't need bridging therapies and consistent with that no patients died while waiting."

Overall, 104 patients were screened, 74 were apheresed, and 69 received treatment with zamto-cel. Of these, 10 patients were not evaluable at the time of the interim analysis, leaving a modified intent-to-treat group of 59.

The median age of patients across the full group (n = 69) was 65 years. Roughly half had an elevated LDH (55.1%) and 53.6% had 2 or more extranodal sites. The median number of prior lines of therapy was 2 for most (75.4%), with the remainder of patients having received 3 or more. A quarter of patients had a prior autologous stem cell transplant (24.6%) and few received bridging therapy, specifically 3 who received steroids and 1 who received radiotherapy. The most delivered lymphodepletion therapy was fludarabine/cyclophosphamide (90%) with 10% of patients receiving bendamustine.

Of the 69 patients enrolled, the cell therapy was successfully manufactured according to product specifications 91.3% of the time. The viability of the cells collected was a median of 96%, the transduction efficiency was 28%, and the median vector copy number was 1.33.

There was a low incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). There were no cases of grade 3 or higher CRS and 4.3% of patients had grade 3 or higher ICANS. Grade 1/2 CRS was seen in 46.4% and grade 1/2 ICANS was experienced by 17.3%. Treatments for CRS/ICANS were given to 34 patients, most commonly steroids (n = 10), Anakinra (n = 2), and tocilizumab (n = 11).

Grade 3 or higher hematologic toxicities were experienced by 62.3% of patients treated with zamto-cel, which consisted of neutropenia/neutrophil count decline (47.8%), anemia/hemoglobin decrease (20.3%), and thrombocytopenia/platelet count decline (11.6%). Grade 3 or higher infections were seen in 4.3% of patients and deaths due to any cause were reported for 5 patients, 3 were due to disease progression, 1 from sepsis, 1 from intestinal perforation, and 1 from COVID-19 pneumonia. There were no cases of secondary malignancies reported.

Upon inspection, antigen loss did not appear to be a driver of progression. Overall, there was no loss of target antigen seen in 82% of patients who progressed. Loss of CD19 alone was seen in 7% of patients, loss of CD20 was seen in 7% of patients, and 1 patient (4%) experienced dual CD19 and CD20 loss. Overall, the CAR T cells were found to proliferate while B cells recovered.

"We need to continue to biopsy people and also to understand what is that mechanism of resistance to this dual-targeted CAR T cell product," said Shah. "We see the preclinical data playing out with the CAR T expansion kinetics. We start to see recovery of B cells, which is important for patients to have immune reconstitution."

Reference
Shah NN, Maziarz RT, Jacobson CA, et al. Interim Results from a Phase 2 Pivotal Study (DALY II USA) of Tandem CD20-CD19-Directed Non-Cryopreserved CAR-T Cells - Zamtocabtagene Autoleucel (Zamto-Cel) in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma. Presented at: ASH 2023 Annual Meeting & Exposition. December 7-10; San Diego, CA. Abstract #68.

Zamtocabtagene autoleucel showed promising early complete response rates and survival outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma.

Tandem CD20/CD19 CAR Zamto-Cel Shows Promise in DLBCL

The CD19-directed CAR T-cell therapy rapcabtagene autoleucel (YTB323) showed high rates of complete remission (CR) and a favorable safety profile for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated findings from a phase 2 study (NCT03960840) presented at 

Across 60 patients with DLBCL who received rapcabtagene autoleucel at a dose of 12.5 x 10

 CAR+ cells at least 25 days before data cutoff, the overall response rate (ORR) was 88.3% (95% CI, 77.4%-95.2%). The CR rate was 65% (95% CI, 51.6%-76.9%). Responses were durable, with 53.9% of patients continuing to respond at 12 months. Of those with a best response of CR, the 12-month duration of response rate was 69.1%. Some patients were able to achieve a CR from their bridging therapy. When these patients were excluded (n = 4), the CR rate with rapcabtagene autoleucel was 62.5%.

"Rapcabtagene autoleucel was associated with responses including a CR in 65% at a median follow-up of 16 months. These responses are durable with 54% of responders still in response at the 12-month mark," lead investigator Peter A. Riedell, MD, from the David and Etta Jonas Center for Cellular Therapy, University of Chicago, said during a presentation of the results. "This treatment was well-tolerated with the safety profile."

Rapcabtagene autoleucel was manufactured using the T-Charge platform from Novartis. This system rapidly manufactures the cells in less than 2 days; however, for the entire process excluding the cell manufacturing, Riedell noted it took roughly 13 days globally and 9 days within the United States. Prior to infusion, lymphodepletion was completed for 3 days using a lower dose (n = 28) and a higher dose (n = 33) of fludarabine/cyclophosphamide (25/250 mg/m

, respectively). Patient characteristics were balanced between groups.

Bendamustine Is an Effective Alternative to Fludarabine-Based Lymphodepletion in LBCL

In the phase 2 study, the median age of patients was 64 years, the IPI score was less than 3 for 54% with the remainder having a score of 3 or more. Double or triple hit mutations were present in a quarter of patients (25.4%), with 39.7% testing negative for a mutation in the MYC/BCL2/BCL6 genes. The remainder had unknown status. More than half of patients (58.7%) were refractory to their last therapy and 41.3% had relapsed after their last line of therapy. A portion (20.6%) were refractory to all lines of therapy received. The primary histology was DLBCL (82.5%) with the remainder having transformed lymphoma. Elevated LDH was seen in 42.9% and the median prior lines of therapy were 2 (73%) or 3 or more (27%). Despite the quick turnaround on the cell therapy, most patients (60.3%) still received bridging therapy.

Across 55 evaluable patients for a 3-month assessment, 55% achieved a CR. The highest rates of CR at 3 months were seen in those who received a prior hematopoietic cell transplant (n = 18). In this group, the CR rate at month 3 was 89%. This was followed by those who  relapsed after their last line of therapy (n = 23), where the CR rate was 70%. In those aged 65 and older (n = 25), the CR rate was 64%.

The median progression-free survival (PFS) was 11.9 months across all patients treated in the study, including those who were recently infused (n = 63). Of those who achieved a CR at month 3 with rapcabtagene autoleucel (n = 30), the median PFS was not yet reached. The 12-month PFS rate in all patients was 48.2%. In those with a CR at month 3, the 12-month PFS rate was 79.3%. For overall survival (OS), the median was not yet reached in any of the patient cohorts. The 12-month OS rate was 83.0% across all evaluable patients and was 100% in those who achieved a CR at month 3.

Across all patients, 98.4% experienced an adverse event (AE) of any grade, with 84.1% experiencing a grade 3 or higher event. Serious AEs were seen in 52.4% of patients and there were 12 deaths in the study, with 6 related to disease progression and 6 from AEs. Deaths were associated with COVID-19 infection (n = 2), acute respiratory failure (n = 1), intestinal hemorrhage (n = 1), septic shock (n = 1), and tumor lysis syndrome (n = 1).

The rates of traditional CAR T AEs were low, with cytokine release syndrome (CRS) of any grade seen in 44.4%. Overall, the rate of grade 3 or 4 CRS was 6.4%. The median time to onset was 8 days, with grade 3 or 4 onset occurring in a median of 7.5 days. The median time from onset to resolution was 6 days, with 53.6% requiring tocilizumab and 25% requiring corticosteroids.

Immune effector cell-associated neurotoxicity syndrome (ICANS) was uncommon, with 3.2% of patients having a grade 1/2 event and 4.8% of patients experiencing a grade 3 or 4 event. The median time to onset was 13 days and the median time to resolution of grade 3 or 4 ICANS was 17 days. For this AE, 80% required treatment with dexamethasone, 40% with methylprednisolone, and 40% with Anakinra.

Cytopenias were commonly reported across all patients treated with rapcabtagene autoleucel (n = 63). For grade 3 or higher events, neutropenia was seen in 38.1%, anemia in 7.9%, thrombocytopenia in 30.2%, and lymphopenia in 42.9%. Neutropenia, anemia, and thrombocytopenia were completely resolved for all patients by month 6, with 73.7% having resolution of lymphopenia at 6 months. There was a single case of grade 3 hemophagocytic lymphohistiocytosis.

Fewer incidences of CRS were seen in the low-dose lymphodepletion group than in the higher-dose arm (39.3% vs 48.5%). Additionally, the rate of grade 3/4 CRS was less in the lower-dose arm (3.6% vs 9.1%). ICANS was more common in the low-dose group than in the high-dose group (14.3% vs 3.0%). Additionally, cytopenias were more common with the lower dose lymphodepletion vs the higher.

"We do notice some differences and importantly to note that patients were assigned to different lymphodepletion chemotherapy groups in a non-randomized way and at different times in the study course, therefore really limiting our ability to compare these two groups," said Riedell. "Collectively, the risk analysis supports the use of lower dose of lymphodepletion therapy prior to infusion."

Reference
Riedell PA, Kwon M, Flinn IW, et al. Rapcabtagene Autoleucel (YTB323) in Patients (Pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL): Phase II Trial Clinical Update. Presented at: ASH 2024 Annual Meeting & Exposition. December 7-10; San Diego, CA. Abstract #67

Rapcabtagene autoleucel showed high rates of durable complete remissions and a favorable safety profile for patients with relapsed/refractory diffuse large B-cell lymphoma.

Rapcabtagene Autoleucel Shows Promise for DLBCL in Updated Phase 2 Data

The efficacy and safety of tabelecleucel (tab-cel; Ebvallo) was confirmed with longer follow-up in updated findings for patients with Epstein–Barr virus (EBV)–associated post-transplant lymphoproliferative disease (PTLD) after failure of rituximab alone or with chemotherapy, according to a presentation open-label phase 3 ALLELE study (NCT03394365) showcased at 

In the open-label study, the overall response rate (ORR) with tab-cel was 50.7%, which included a complete response (CR) rate of 28.0%. The median time to response was 1.1 months and the estimated duration of response was 23.0 months. In those who responded, the median progression-free survival (PFS) was 23.9 months, and the 12-month PFS rate was 74.2%. In all patients, the median overall survival (OS) with tab-cel was 18.4 months, and the 12-month OS rate was 55.7%.

"The ALLELE study data from this larger cohort confirm the previously reported data for both safety and efficacy of tab-cel. These are very promising outcomes," lead investigator Armin Ghobadi, MD, Division of Oncology, Washington University School of Medicine, said during a presentation of the results. "It is very safe. Few serious adverse events were found."

biologics license application for tab-cel

 as a treatment for EBV-positive PTLD, based on earlier findings from the ALLELE study that were published in 

 Based on the standard timelines established under the Prescription Drug User Fee Act, the FDA has a target action date of January 15, 2025, for the application.

Tab-cel is an off-the-shelf, non-genetically modified, allogenic EBV-specific T-cell immunotherapy. The cell is manufactured from healthy unrelated donors and cryopreserved in a biobank across several HLA profiles. The exact treatment is selected based on each patients HLA characterization and compatibility. No lymphodepletion or pretreatment is required.

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Two groups of patients were assessed in the phase 3 study, namely those who received hematopoietic stem cell transplant (HCT) and failed rituximab (n = 26) and those with solid organ transplant (SOT) who either failed rituximab alone (subgroup A) or rituximab plus chemotherapy (subgroup B). Tab-cel was administered to both SOT and HCT groups at 2.0 x 10

 cells/kg on days 1, 8, and 15, with clinical and radiologic assessment through day 28.

Patients could receive multiple treatment cycles until best response was achieved. If a non-response was seen, they also could be switched to another HLA lot. The median number of tab-cel cycles was 2 and the median number of infusions was 6. Overall, 3 lots of treatment were utilized. Most patients were infused in the outpatient setting (66.9%).

Patients in all groups had similar characteristics. The median age was 44.4 years. The ECOG performance score was 1, with a score of 2 or more seen in roughly a quarter of patients (26.5%). Extranodal disease was seen in three-fourths of patients (74.7%) and nearly all patients were deemed as high (42.6%) or intermediate rick (50%) by PTLD prognostic index. The PTLD morphology was primarily diffuse large B-cell lymphoma (69.3%).

The median time from diagnosis to first tab-cel administration was 4.6 months. The median number of prior therapies was 1 (range, 1-5), which included rituximab monotherapy for most patients (86.7%). Prior chemotherapy was received by 46.7% of patients and a combination of rituximab and chemotherapy was given to 37.3%. There were 3 patients who received prior immunotherapy. The most common transplant types were kidney (28.6%), heart (24.5%), and multivisceral (20.4%).

In the HCT group, the ORR was 50.0% with an estimated duration of response of 19.0 months. The CR rate was 30.8%. In the SOT group, the ORR was 51.0%, with a CR rate of 26.5%. The duration of response was 23.0 months.

In those who showed a response, the 12-month OS rate was 78.7% and the median OS was not yet reached. In those who did not respond, the 12-month OS rate was 28.2% and the median OS was 3.1 months.

Most treatment-emergent serious adverse events (TESAEs) were not treatment related, Ghobadi said. Overall, just 8% of patients experienced a TESAE related to tab-cel.

"For treatment-emergent AEs of special interest, there was no tumor flare, no cytokine release syndrome, no ICANS," said Ghobadi. "Graft-vs-host disease happened in 2 patients both in patients who received prior transplant. Bone marrow/organ rejection was seen in 3 patients, all were treated and it was resolved in these patients."

Atara Biotherapeutics, the developer of tab-cel, is also exploring the agent in the phase 2 EBVision trial (NCT04554914), which is examining tab-cel across several cohorts for EBV-positive diseases. If positive, findings from this multicohort study could support label expansion beyond PTLD, according to Atara's President and Chief Executive Officer Pascal Touchon in July 2024.

 The study was initiated in 2021 and has a primary completion date listed as June 2027.

References
1. Ghobadi A, Baiocchi R, Beitinjaneh AM, et al. Updated Clinical Results: A Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Recipients with Epstein–Barr Virus-Driven Post Transplant Lymphoproliferative Disease after Failure of Rituximab or Rituximab Plus Chemotherapy. Presented at: ASH 2024 Annual Meeting & Exposition. December 7-10; San Diego, CA. Abstract #70.
2. Mahadeo KM, Baiocchi R, Beitinjaneh A, et al. Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein–Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial. Lancet Oncol. 2024;25(3):376-387.
3. Atara Biotherapeutics Announces U.S. FDA Acceptance and Priority Review of the Biologics License Application for Tabelecleucel (Tab-cel®) for the Treatment of Epstein-Barr Virus Positive Post-Transplant Lymphoproliferative Disease. July 17, 2024. Accessed December 6, 2024. https://investors.atarabio.com/news-events/press-releases/detail/356/atara-biotherapeutics-announces-u-s-fda-acceptance-and

With an FDA deadline pending in January, tabelecleucel remained safe and effective with longer follow-up for Epstein–Barr virus-associated post-transplant lymphoproliferative disease.

John Brandsema, MD

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