2024 Tandem Meetings Transplantation & Cellular Therapy Meetings of ASTCT® and CIBMTR®

Matthew Daniels, PharmD, BCOP, Bone Marrow Transplant Pharmacist, Oklahoma University Medical Center

Introduction:

The Tandem Meetings is an annual in-person conference hosted by the American Society for Transplantation and Cellular Therapy (ASTCT®) and the Center for International Blood and Marrow Transplant Research (CIBMTR®). Individuals from around the world come to share and learn about the latest updates in transplantation and cellular therapy. This year the meeting was held on February 21-24, 2024, in San Antonio, Texas.

Experts in their field presented a wide variety of topics including groundbreaking research, updates in therapies and molecular testing and more. Because ASTCT and CIMBTR has a large variety of healthcare professionals involved in their organizations, there were multiple presentations geared specifically for nurses, pharmacists, mid-levels, and physicians alike! Below are a few highlights from the pharmacy track.

Highlight 1: Management of Cytopenia Post Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: a US and UK perspective1

In this presentation, Dr. Mary McGann and Brijesh Gautama discussed the incidence and etiology of cytopenias after CAR T-cell therapy as well as predicting those at risk and treatment strategies in the United States and United Kingdom. Cytopenia in one or more cell lineage is the most common side effect from CAR-T. It is often bi- or tri-phasic and can be classified as early (<30 days), prolonged (30-90 days), or persistent (> 90 days). Real world data from EBMT (European Society for Blood and Marrow Transplantation) demonstrated a 9% and 12.1% incidence of grade > 3 cytopenia at 30 and 100 days, respectively. Granulocyte colony stimulating factors (G-CSF) are commonly used, however they can be transient and may need to be restarted when patients become neutropenic again. Treatment with prophylactic G-CSF showed faster neutrophil engraftment, but no difference in recurrent neutropenia and an increase in grade > 2 cytokine release syndrome (CRS). However, multiple studies show that G-CSF post CAR-T infusion (as early as Day +2) may shorten neutropenia with no increase in CRS. Thrombopoietin receptor (TPO) agonists have also been evaluated for use in thrombocytopenia post CAR-T. While no optimal timing or dosing known, most data has been with eltrombopag at a dose of 75-150 mg daily. Use could be considered for patients experiencing thrombocytopenia beyond 30 days of CAR-T. Stem cell boost is another option, but the optimal timing and cell dose has yet to be found and it may not work for patients with an active infection.

Highlight 2: GENEie in a Bottle: Gene Therapy for Hemoglobinopathies2

Dr. Alexis Kuhn spoke on the gene therapies available for β-thalassemia and sickle cell disease (SCD) in pediatric patients. Her presentation focused on describing the mechanisms of action of approved and investigational gene therapies, medication-specific considerations for each product, as well as examining their place in therapy. Because β-thalassemia and SCD both result from mutations in the HBB gene, both

could be treated if this gene is manipulated. Currently, the two approaches are called gene addition and gene editing. Gene addition inserts a functional HBB gene into progenitor stem cells via a lentiviral vector. Products that work through gene addition include betibeglogene autotemcel (beti-cel) and lovotibeglogene autotemcel (lovo-cel) for transfusion dependent thalassemia (TDT) and SCD, respectively. Gene editing can either disrupt the malfunctioning gene which upregulates fetal hemoglobin production, or it can correct the point mutation resulting in restored normal hematopoiesis. Exagamglogene autotemcel (exa-cel) is FDA approved for SCD and works via gene disruption. Gene correction products remain in clinical trials. The data for these FDA-approved products demonstrated ~90% patients met the primary outcome of either transfusion independence or no veno-occlusive crisis for > 12 months in TDT and SCD in their respective studies. As the process of administration is similar to an autologous transplant, the main side effects seen stemmed from the busulfan conditioning. Dr. Kuhn finished her presentation discussing the differences in mobilization and iron chelation between products. Providers should consult the package insert to ensure proper procedures are being followed for mobilization, chelation, and busulfan dosing.

Highlight 3: Taking a Bite out of CAR-T: Debating Use of CAR T-cell Therapy Vs Bispecific Antibodies in Lymphoma3

Dr. Emilie Aschenbrenner and Dr. Katie Gatwood debated the current literature to describe the sequencing and place in therapy for CAR-T and Bispecific Antibodies (BsAbs) in relapsed/refractory large B-cell lymphoma (r/r LBCL). Within the past few years, three CAR-T products have been approved for LBCL in the third line setting: axicabtagene ciloleucel, Tisagenlecleucel, and Lisocabtagene maraleucel. These CAR-T products can be appealing options given the excellent long-term follow up data associated with them. The two FDA-approved BsAbs for r/r LBCL are epcoritamab and glofitamab. Epcoritamab is a subcutaneous injection that can be given until progression of disease and demonstrated an ORR of 63.1% in the EPCORE NHL-1 trial. Glofitamab is an IV infusion that demonstrated an ORR 52% in the NP30179 trial with a maximum duration of 12 cycles. The rate of CRS was low and peaked within the first cycle. CAR-T and BsAbs both have limitations. CAR-T has manufacturing time delays and failure, more toxicity, higher upfront cost, more requirements for caregiver support, and more difficult to access. Whereas BsAbs are still new and have a lack of survival data, unclear duration of therapy, long-term cost, and are dependent on endogenous T-cell function. Research into optimal sequencing of CAR-T and BsAbs is still ongoing. Currently, limited data suggests similar CR rates in BsAbs after CAR-T; however, responses were much lower in patients refractory to CAR-T. Early data suggests CAR-T efficacy may be preserved in patients treated with prior BsABs.

Highlight 4: Post-transplant Maintenance Therapy for Acute Myeloid Leukemia (AML)4

Dr. Andrew Lin reviewed the options for post-transplant maintenance therapy for AML. He evaluated the relative efficacy and limitations of various therapies and described current investigative strategies. Maintenance therapy has been challenging in the past due to the risk of cytopenias, immunosuppression, and toxicity. While maintenance can be challenging, ~40% of patients with AML relapse post-transplant and have poor prognosis, emphasizing the need for maintenance. Oral and IV hypomethylating agents have been studied. A meta-analysis including IV azacitidine and decitabine demonstrated a Hazard ratio of 0.45 for death. However, other prospective trials not included in this review demonstrated no overall survival (OS) benefit. Other targetable therapies, such as FLT3 inhibitors, IDH1/2 inhibitors, and BCL-2 inhibitors have been studied as well. Sorafenib demonstrated a relapse free survival benefit and an overall survival benefit at 42 months for FLT3 positive patients, however, nearly 50% of patients required dose reductions due to side effects. It is the only FLT3

inhibitor to have a recommendation from any compendium (EBMT guidelines). Gilteritinib also showed a relapse free survival benefit in patients with minimal residual disease (MRD), but not MRD negative patients. Eprenetapopt is a novel first in class small molecule p53 reactivator that has been studied in TP53 positive patients. A small trial demonstrated eprenetapopt and azacitidine have a 1-year OS probability of 78.8% with manageable toxicities. Ultimately, there is limited data for the ideal maintenance therapy. Hypomethylating agents and targeted therapies are all potential options. Cytopenias remain the biggest obstacle for maintenance therapy.

Conclusion:

The 2024 Tandem Meetings provided a wide array of topics and discussions that aided in the advancement of care for patients undergoing transplantation or cellular therapy. Some of the presentations not discussed include: how to establish oneself in clinic, updates from the annual ASH (American Society of Hematology) meeting in December, challenges in atypical/CNS chronic GVHD, updates in CMV management, viral specific T-cells, post-transplant cyclophosphamide best practice panel, reduced intensity conditioning regimen debate, and off-label administration of oral medications which led to an open dialogue where audience members shared their experiences crushing certain medications. The next Tandem Meetings will be held on February 12-16, 2025, in Honolulu, HI.

References:

1.McGann M, Gautama B. Management of Cytopenia Post CAR T-Cell Therapy: a US and UK perspective. Session presented at: 2024 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT™ and CIBMTR®; February 23, 2024; San Antonio, TX.

2.Kuhn A. Geneie in a Bottle: Gene Therapy for Hemoglobinopathies. Session presented at: 2024 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT™ and CIBMTR®; February 23, 2024; San Antonio, TX.

3.Aschenbrenner E, Gatwood KS. Taking a Bite out of CAR-T: Debating Use of CAR T-Cell Therapy Vs Bispecific Antibodies in Lymphoma. Session presented at: 2024 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT™ and CIBMTR®; February 24, 2024; San Antonio, TX.

4.Lin A. Post-Transplant Maintenance Therapy for Acute Myeloid Leukemia. Session presented at: 2024 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT™ and CIBMTR®; February 24, 2024; San Antonio, TX.

Recommended Readings:

1.Jain T, Olson TS, Locke FL. How I treat cytopenias after CAR T-cell therapy. Blood. 2023 May 18;141(20):2460-2468.

2.Drillet G, Lhomme F, De Giubert SD, Manson G, Houot R. Prolonged thrombocytopenia after CAR T-cell therapy: the role of thrombopoietin receptor agonists. Blood Advances. 2023 Feb 28;7(4):537-540.

3.Kanter J, Liem RI, Bernaudin F, et al. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021;5(18):3668-3689.

4.Cappellini, M.D., Farmakis, D., Porter, J. Taher, A. et al. 2021 Guidelines for the Management of Transfusion Dependent Thalassaemia (4th edition – Version 2.0). Thalassemia International Foundation. 2021. < https://thalassaemia.org.cy/publications/tif-publications/guidelines-for-the-management-of-transfusion-dependent-thalassaemia-4th-edition-2021-v2/>

5.Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large b-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231.

6.Crochet G, Audrey C, Bachy E, et al. CAR T-cell therapy remain effective in patients with relapse/refractory B-cell non-Hodgkin lymphoma after bispecific antibodies exposure: results of a lysa study based on the descar-T registry. Blood. 2022;140(suppl 1):4639-4641.

7.DeFilipp Z, Chen YB. How I treat with maintenance therapy after allogeneic HCT. Blood. 2023;141(1):39-48.

8.Senapati J, Kadia TM, Ravandi F. Maintenance therapy in acute myeloid leukemia: advances and controversies. haematol. Published online May 4, 2023.