The cellular therapy community has long recognized inequality in access to treatment and disparities in treatment outcomes based on patient race, ethnicity, and socioeconomic status. [1][2] It is no longer enough to recognize the problem exists. As the late John Lewis stated, “If you see something that is not right, not fair, not just, you have a moral obligation to do something about it.” The cellular therapy community, which includes hematopoietic cell transplantation (HCT), must advance efforts to end these inequities.

The ACCESS Initiative aims to do just that. The National Marrow Donor Program (NMDP)/Be The Match and the American Society for Transplantation and Cellular Therapy (ASTCT) formed the ACCESS Initiative in July 2022. The initiative brings the HCT/cellular therapy community together to identify and implement practice and policy changes that will reduce barriers to HCT/cellular therapy and improve outcomes for patients.

Inequality in HCT/cellular therapy is multi-faceted and the problems are entrenched in the United States healthcare system. Solving the issues to create meaningful, widespread change requires active and sustained engagement of everyone involved in the care and support of patients who need HCT/cellular therapy. This includes HCT/cellular therapy clinicians and institutions, program administrators, health policy and health equity experts, health services researchers, payer organizations, and federal and state stakeholders.

Disparities remain despite treatment advances
Over the last decade, the HCT/cellular therapy community made treatment advances that allow more patients to proceed to treatment. In allogeneic HCT, this includes the ability to transcend the human leukocyte antigen (HLA) barrier for patients who do not have a fully matched related or unrelated donor—an issue which disproportionately impacts patients who are ethnically diverse. [3]

The 15-Mismatched unrelated donor (MMUD) clinical trial demonstrated that patients without a fully matched donor can proceed to HCT with good outcomes. [4][5] Research using mismatched unrelated donors continues today with the ACCESS clinical trial (NCT04904588) that is currently enrolling patients. [6]

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In April 2023, the US Food and Drug Administration (FDA) approved an allogeneic cord blood-based cellular therapy that helps reduce the risk of infection by quickening neutrophil recovery for patients who receive HCT using cord blood as the graft source. [7] Compared to allogeneic HCT overall, a higher proportion of patients who are ethnically diverse receive allogeneic cord blood HCT than those who are non-Hispanic white. [8]

In addition, six chimeric antigen receptor (CAR) T-cell therapies have received FDA approval since 2017. Many more allogeneic and autologous cell and gene therapies for hematologic malignancies and disorders are in clinical trials. [9]

Despite these promising advances, access and outcomes for HCT and cellular therapy are not equal.

For example, a CIBMTR (Center for International Blood and Marrow Transplant Research) analysis of the impact of neighborhood poverty exposure on pediatric HCT outcomes found neighborhood poverty was associated with higher transplant-related mortality (TRM) in the malignant disease cohort. Those receiving Medicaid had lower overall survival and higher TRM compared to children with private insurance. [10]

A retrospective analysis of US unrelated donor (URD) searches of the Be The Match Registry found that patients who were non-Hispanic white were more likely to receive HCT within six months of active search initiation than patients who were Black or African American (45% versus 27%; p<0.001). [11]

The landscape is similar in CAR-T therapy. A retrospective study using the Vizient® clinical database revealed disparities based on race and ethnicity, socioeconomic status, and insurance status. For example, patients who were Black and African American were two times less likely to receive CAR-T therapy, less than 12% of patients who received CAR-T were from low-income neighborhoods, and those who had Medicaid insurance or who were uninsured were less likely to receive CAR-T therapy. [12]

Another study by the Pediatric World CAR Consortium focused on outcomes for pediatric patients who were Black and African American. Low representation of Black and African American patients (5.5%) was a study limitation, however, Black and African patients had lower rates of complete remission (57% vs. 86%) and overall survival at 6 months (43% vs. 86%) and one year (43% vs. 73%) after receiving CAR-T. [13]

With the number of treatment options available today, continued access and outcomes disparities are unacceptable. The ACCESS Initiative is a starting point for the HCT/cellular therapy and broader hematology/oncology communities to take collective steps forward to overcome these issues deeply rooted in the US healthcare system.

The initiative has three focus areas to start: awareness, poverty, and racial and ethnic inequity. [1]

Increasing awareness among hematologists/oncologists and patients
Awareness among healthcare providers and patients is one barrier to HCT/cellular therapy access, which can then lead to outcomes disparities if treatment is delayed.

Hematologists/oncologists at community practices or academic institutions that do not provide HCT/cellular therapy hold the key to patient access to treatment as they refer patients to transplant and cellular therapy centers. However, they may not be aware of new standards of care in HCT and cellular therapy. [14][15]

This is a key area of focus for the ACCESS Initiative Awareness Committee, which aims to increase awareness among hematologists/oncologists about new research and treatment options.

For example, the committee launched a Physician Exchange program. This program fosters discussion between hematologists/oncologists and HCT/cellular therapy physicians on how to support patients across the care continuum. This starts at patient diagnosis and continues through the patient’s return to the hematology/oncology practices post-HCT/cellular therapy treatment.

Along with fostering partnerships and connections between hematology/oncology practices and transplant/cellular therapy centers, the committee will provide hematology/oncology practices with education and improve access to information about current research.

Awareness also must extend to the patient community. Informed patients are empowered patients who can advocate for themselves and make educated decisions about their care. Therefore, the Awareness Committee is working with national disease-specific groups and health-focused community organizations within the patient community. It will raise awareness about treatment options and share support information via joint campaigns and local outreach efforts. [1][16]

Reducing poverty-related barriers through patient, center, and policy initiatives
Poverty is a persistent challenge in the US and impacts healthcare due to socioeconomic determinants of health and factors such as inadequate or no insurance coverage which limits access to optimal care.

Data from the US Census Bureau show the widespread impact. In 2021, 37.9 million people—just over the total population of Texas and Washington combined—were living in poverty; approximately 27.2 million people—more than the population of Florida—were without health insurance. [17][18][19]

The ACCESS Initiative will focus where it can make a difference by developing patient-, center-, and policy-related initiatives that can improve patient access to care and survival.

For example, covered services and payment models vary by plan and, in the case of Medicaid, by state. The Poverty Committee aims to identify patients at high risk of unfavorable outcomes due to socioeconomic adversity and improve understanding of state-by-state HCT and cellular therapy Medicaid coverage. It will use clinician-led, grassroots efforts to advocate for state and federal legislation that helps patients access care. [1][16]

Biomarker testing coverage is a service where payment models vary and where advocacy can make a difference. HLA typing and testing is a biomarker test used in allogeneic HCT. Without HLA typing, a donor search cannot begin. That directly impacts a patient’s ability to access care. Many states have introduced legislation that would require health insurance coverage for biomarker testing. [20]

In addition, the Poverty Committee is prioritizing the identification of access barriers using claims data on patients from pre-diagnosis through post-treatment as well as identifying and highlighting psychosocial and financial resources available throughout the HCT/cellular therapy community. [16]

Improving access and outcomes regardless of race and ethnicity
Race and ethnicity are intertwined with other factors that influence health inequities including individual, systemic, and societal barriers to healthcare. These inequities impact patients from diagnosis through post-HCT/cellular therapy care. In order to find solutions, those barriers must be addressed.

As a starting point, the ACCESS Initiative Racial and Ethnic Inequity Committee will focus on patient knowledge, data optimization, and workforce development. Ultimately, the committee aims to improve equity in access and outcomes for all HCT and cellular therapy recipients regardless of their race or ethnicity.

As with awareness, a patient’s lack of knowledge of treatments available to them can hinder their access to care. However, it is not enough to have educational materials available for patients. Those materials must be culturally sensitive and easy to access.

To achieve this, the Racial and Ethnic Inequity Committee is reviewing patient educational resources for cultural sensitivity by gathering input directly from those who are ethnically diverse. In addition, it aims to create a new index of easy-to-find patient education resources.

Having culturally sensitive materials is not enough. Patients must also receive culturally sensitive care. This includes a patient identifying with their physicians and other caregivers. To improve representation in HCT/cellular therapy, the committee plans to create a pipeline program for trainees who are underrepresented in the HCT/cellular therapy field.

Finally, addressing systemic barriers to care requires a true understanding of who is and, importantly, who is not being served. Data optimization is critical for gaining this knowledge.

The committee will pilot a data-collection program with select centers from different regions of the country. These data will provide a better picture of the number of potential patients in the center’s catchment area as well as who did or did not proceed to HCT/cellular therapy.

Center-level health-equity metrics can provide insights into underserved populations and offer areas of focus for access improvement. [1][16]

Overcoming the challenges requires sustained engagement
Access and outcomes inequities did not happen overnight and change will take time. However, to move the needle, the HCT/cellular therapy community must stop talking about the problem and must start taking steps to solve the problem.

After treatment, patients have a long road to recovery but transplant day—called “day zero”—is also a new beginning. The ACCESS Initiative is day zero for the HCT/cellular therapy community. It is time to begin the long road to overcome long-standing barriers to access and reduce inequities for patients.

Clinical trials
HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide (ACCESS) – NCT04904588

References
[1] Auletta JJ, Sandmaier BM, Jensen E, et al. The ASTCT-NMDP ACCESS Initiative: a collaboration to address and sustain equal outcomes for all across the hematopoietic cell transplantation and cellular therapy ecosystem. Transplant Cell Ther. 2022;28(12):802-809. doi: 10.1016/j.jtct.2022.09.020
[2] Hong S, Majhail NS. Increasing access to allotransplants in the United States: the impact of race, geography, and socioeconomics. Hematology Am Soc Hematol Educ Program. 2021;2021(1): 275-280. doi: 10.1182/hematology.2021000259
[3] Spellman, SR. Hematology 2022–what is complete HLA match in 2022? Hematology Am Soc Hematol Educ Program. 2022;2022(1): 83-89. doi: 10.1182/hematology.2022000326
[4] Shaw BE, Jimenez-Jimenez AM, Burns LJ, et al. National Marrow Donor Program–Sponsored multicenter, phase ii trial of HLA-mismatched unrelated donor bone marrow transplantation using post-transplant cyclophosphamide. J Clin Oncol. 2021;39(18):1971-1982. doi: 10.1200/JCO.20.03502
[5] Shaw BE, Jimenez-Jimenez AM, Burns LJ, et al. Three-year outcomes in recipients of mismatched unrelated bone marrow donor transplants using post-transplantation cyclophosphamide: follow-up from a National Marrow Donor Program-sponsored prospective clinical trial. Transplant Cell Ther. 2023;29(3):208.e1-208.e6. doi: 10.1016/j.jtct.2022.12.017
[6] Al Malki MM, Devine SM, Shaw BE, et al. Access: a multi-center, phase ii trial of HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplantation cyclophosphamide for patients with hematologic malignancies. Blood. 2022;140(S1):7591-7593. doi: 10.1182/blood-2022-162581
[7] U.S. Food and Drug Administration. FDA Approves Cell Therapy for Patients with Blood Cancers to Reduce Risk of Infection Following Stem Cell Transplantation. Online. Last accessed on May 8, 2022.
[8] Auletta J.J., Kou J., Chen M., Shaw B.E. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides, 2021. Online Last accesses on May 22m 2023.
[9] National Cancer Institute. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. Updated March 10, 2022. Online. Last accesses on March 31, 2023. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
[10] Paulson K, Brazauskas R, Khera N, et al. Inferior access to allogeneic transplant in disadvantaged populations: a Center for International Blood and Marrow Transplant Research analysis. Biol Blood Marrow Transplant. 2019;25(10):2086–2090. doi: 10.1016/j.bbmt.2019.06.012
[11] Dehn J, Chitphakdithai P, Shaw BE, et al. Likelihood of proceeding to allogeneic hematopoietic cell transplantation in the United States after search activation in the National Registry: impact of patient age, disease, and search prognosis. Transplant Cell Ther. 2021;27(2):184.e1-e13. doi: 10.1016/j.bbmt.2020.10.004
[12] Ahmed N, Shahzad M, Shippey E, et al. Socioeconomic and racial disparity in chimeric antigen receptor T cell therapy access. Transplant Cell Ther. 2022;28(7):358–364. doi: 10.1016/j.jtct.2022.04.008
[13] Baggott C, Kunicki M, Pacenta HL, et al. Inferior outcomes among black patients with childhood acute lymphoblastic leukemia following tisagenlecleucel. The 2021 Transplantation and Cellular Therapy Meetings Digital Experience. February 8-12. 2021.
[14] Pidala J, Craig BM, Lee SJ, Majhail N, Quinn G, Anasetti C. Practice variation in physician referral for allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2013;48(1): 63-67. doi: 10.1038/bmt.2012.95
[15] Meyer C, Mau L-W, Murphy EA, et al. Addressing knowledge gaps in acute myeloid leukemia to improve referral for hematopoietic cell transplantation consultation. J Natl Compr Canc Netw. 2019;17(12): 1473-1481. doi: 10.6004/jnccn.2019.7327
[16] Davies SM, Auletta JJ, Arnold SD, et al. ASTCT/NMDP Access Initiative. Symposium at: Transplantation and Cellular Therapy Tandem Meetings of ASTCT and CIBMTR; February 18, 2023; Orlando, FL.
[17] Creamer J, Shrider EA, Burns K, Chen F. Poverty in the United States: 2021. United States Census Bureau. September 13, 2022. Online. Last accessed on March 31, 2023.
[18] United States Census Bureau. State Population Totals and Components of Change: 2020-2022. Updated March 23, 2023. Online. Last accessed March 31, 2023.
[19] Keisler-Starkey K, Bunch LN. Health insurance coverage in the United States: 2021. United States Census Bureau. September 13, 2022. Accessed March 31, 2023. https://www.census.gov/library/publications/2022/demo/p60-278.html
[20] Association of Community Cancer Centers. State Legislation Requiring Coverage of Biomarker Testing Gains Momentum. Online. Last accessed on May 8, 2023.

Jeffery J. Auletta, MD, and Stella M. Davies, MBBS, PhD, MRCP, are Co-Chairs of the ACCESS Initiative.

Featured image by Clay Banks on Unsplash. Used with permission.


How to cite:

DOI: https://doi.org/10.14229/onco.2023.05.22.001.

Jeffery J. Auletta, MD 1, Stella M. Davies, MBBS, PhD, MRCP2
It’s Time to Stop Talking About Cellular Therapy Disparities and Take Action – Onco Zine – The International Oncology Network; May 22, 2023. DOI: 10.14229/onco.2023.05.22.001.

1 Center for International Blood and Marrow Transplant Research (CIBMTR).
2 Cincinnati Children’s Hospital Medical Center

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