Navigating the Complex Landscape of Sickle Cell Gene Therapy: Operational Challenges and Collaborative Solutions

Transfusion medicine is a critical component of the treatment of hemoglobinopathies such as sickle cell disease (SCD). However, with a complicated and multifaceted process of hematopoietic stem cell collection for gene therapy, health care professionals (HCPs) may encounter challenges that require innovative solutions, according to a session at the American Society for Transplantation and Cellular Therapy's (ASTCT) second annual Gene Therapy Summit in Boston.¹

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Speakers during the session included session chair Suzanne Thibodeaux, MD, PhD, Washington University; Yvette Tanhehco, MD, PhD, MS, associate professor of pathology and cell biology, Columbia University Irving Medical Center; Patricia Shi, MD, medical director and vice president, New York Blood Center Enterprises; and Cyril Jacquot, MD, PhD, associate chief of pathology and laboratory medicine, Children's National Hospital. Throughout the session, the speakers sought to explore how the strengths of transplantation centers can be leveraged to deliver safe and effective gene therapies.¹

Challenges and Solutions During the Gene Therapy Process

Tanhehco began the discussion by outlining the operational and logistical challenges associated with gene therapy for patients with SCD. As an HCP deeply embedded in the process, Tanhehco addressed real-life obstacles she has encountered in her practice while providing practical solutions that can be implemented across specialties. In SCD, a beta hemoglobinopathy caused by a point mutation, sickled red blood cells are fragile, necessitating careful execution and patience throughout the administration of gene therapy.¹

The FDA approved 2 commercial gene therapy products to treat patients with SCD ages 12 and older: lovotibeglogene automtemcel (Lyfgenia; Bluebird Bio, Inc) and exagamglogene autotemcel (Casgevy; Vertex Pharmaceuticals). These were the first cell-based gene therapies for this indication. With these products, a patients’ own stem cells must be collected, and must then undergo myeloablative conditioning to prepare their bone marrow for the modified stem cells included in Lyfgenia and Casgevy treatments. A series of critical steps are involved regarding preparation and administration of these therapies, including red blood cell exchange, mobilization, stem cell collection, and drug infusion.^1,2

For each step, Tanhehco provided real-world examples of challenges that may be encountered and viable solutions to tackle these obstacles. During the red blood cell exchange process, which is performed to improve oxygen delivery and enhance tissue perfusion, HCPs must ensure there is adequate personal on hand to perform the exchange—with correspondingly adequate chair capacity—while providing sufficient notice to blood suppliers so donor red blood cells can be procured without delay. Next, plerixafor (Mozobil; Sanofi) is utilized to mobilize hematopoietic stem cells into the peripheral blood for collection. Challenges include the narrow time frame between the administration of plerixafor and collection—which can be as short as 3 hours in SCD—and, simply, poor mobilization with a standard dose. Providers can consider increasing the dose of plerixafor if mobilization issues are encountered, while ensuring close communication with the apheresis team will help optimize the process.¹

Perhaps the most critical aspect of gene therapy is performing stem cell collection. One of the most common obstacles to efficient collection is poor venous access, which Tanhehco notes could require central catheters. Further, HCPs may encounter interruptions due to delayed product send-outs, which could burden patients seeking clarity. Delays could also be created due to the need to adjust instrument settings for patients with SCD and pain crises that they may experience. Educating staff and patients on what might be expected during the stem cell collection procedure is essential to ensuring both operator competency and patient comfort. Staff should also be educated on how to manage pain crises as they occur, including through prophylactic red cell exchange, pain medications, or, for citrate toxicity, calcium infusions before or during collection.¹

“It's key to optimize the patient condition to avoid any delays in starting that process,” Tanhehco said during the session.¹

Once collection is complete, the drug manufacturing and infusion processes can begin. With challenges including limited storage space, the risk of liquid nitrogen freezer failure, and the very short thaw-to-infusion times—as low as 20 minutes for exagamglogene autotemcel—appropriate staff allocation, advanced planning, and patient optimization are critical, Tanhehco explained.¹

Ultimately, “autologous transplantation with gene therapy is a curative option for patients with SCD,” Tanhehco concluded.¹

Optimizing Patients for Mobilization and Collection

Building off the listed challenges that can be encountered during mobilization and collection, Shi’s focus during the session sought to explain strategies for patient optimization prior to stem cell mobilization and collection. Shi noted that a key predictor of response in patients undergoing gene therapy are baseline CD34+ counts, of which higher levels may predict responses following use of plerixafor. However, in SCD, high CD34+ counts could be a sign of inflammation or stress. Multiple interventions are available to assist in the mobilization process in SCD and reduce vascular abnormalities.^1,3

The use of hydroxyurea, a medication used to reduce pain crisis frequency and the need for blood transfusions in patients with SCD, may induce a large reduction in the number of blood cells in bone marrow, making it difficult for plerixafor to properly mobilize such cells. Shi noted that, to avoid hemopoietic stem cell exhaustion, hydroxyurea can be stopped for 2 weeks prior to collection to allow for succifient recovery from its myelosuppressive effects. Accordingly, transfusions—ideally beginning around 60 days prior to mobilization—can help reverse vascular abnormalities and prime the patient for mobilization. A red blood cell exchange performed a day before collection can also decrease viscosity and inflammation, according to Shi.¹

One major concern Shi discussed was pain management, as crises could interfere with stem cell collection. Although it is preferred to continue SCD treatment if it is not inducing any myelodepressive effects, “Do we need to stop drugs that are not myelodepressive?” Shi questioned. If necessary, agents including opioids or hypotonic saline could serve as crucial tools in making patients more comfortable during the arduous process. For patients who are heavily alloimmunized, Shi explains that voxelotor (Oxbryta; Pfizer)—previously withdrawn by Pfizer due to safety concerns but approved for SCD treatment—could be utilized as an oxygen affinity modulator in patients who are heavily alloimmunized. Shi noted the manufacturer is trying to bring the agent back to market.¹

Overall, to heighten stem cell collection efficiency and yield, Shi notes that effective plerixafor administration is key—specifically, optimal collection time is essential for a robust yield. Research indicates that the optimal collection time, depending on patient tolerance and CD34+ count elevation, could be between 4 and 10 hours after plerixafor. For increasing the yield, a higher dose of plerixafor is safe and could be effective, while other adjunctive agents including aspirin and crizanlizumab under investigation for their impacts in mobilization.¹

Pediatric Experiences in Gene Therapy

Jacquot concluded the session by outlining real-world pediatric experiences with gene therapy collections for patients with SCD or beta-thalassemia, another blood disorder that impacts hemoglobin production and could lead to anemia. Jacquot noted that the current discussion occurs as his institution, Children’s National Hospital, has seen a significant increase in gene therapy collections, moving from 2 being performed in 2023 to 38 in 2025 so far. With greater proliferation of gene therapy in pediatrics, Jacquot stressed the importance of multi-disciplinary coordination among the pharmacy, radiology, hematology, apheresis, and manufacturing teams regarding patient concerns and scheduling.¹

“There are a lot of players that need to let us know which dates work so the patient can get everything in order,” Jacquot explained, noting that any delays could disrupt the mobilization process and delay collection.¹

Multiple tools are available for HCPs to optimize the collection process in pediatrics, according to Jacquot. For example, using a higher inlet producing gene therapy job aids to inlet:anticoagulant (AC) ratio and target darker collection colors to improve efficiency, as Jacquot acknowledged the distinct layering of stem cells in patients with SCD. More practical methods include the creation of job aids for apheresis staff to utilize, undergoing peer checks, and obtaining same-day CD34+ yield results.¹

Once again, patient comfort is a paramount concern, with Jacquot acknowledging that common adverse events may include line discomfort during the collection process, hypocalcemia, and possible hypertension, which he noted was observed in a series of pediatric patients. Additionally, with allergic reactions to mobilizing agents possible, Jacquot noted that patients are now kept overnight following the collection process for observation. He also acknowledged that this process could cause undue stress for families, especially if a patient needs to return for more collection—above all, providing them counseling and comfort is essential to a seamless procedure.¹

REFERENCES

1. Thibodeaux S, Tanhehco, Shi P, Jacquot C. Concurrent 1: Mobilization and Apheresis for Gene Therapy: 201. Presented: American Society of Transplantation and Cellular Therapy Gene Therapy Summit 2025. September 11, 2025. Joseph B. Martin Conference Center. Boston, Massachusetts.

2. FDA. FDA approves first gene therapies to treat patients with sickle cell disease. Published December 8, 2023. Accessed September 11, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease

3. Ketterer N, Salles G, Raba M, et al. High CD34(+) cell counts decrease hematologic toxicity of autologous peripheral blood progenitor cell transplantation. Blood. 1998;91(9):3148-3155. PMID: 955836