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Reinhardt, B.; Lee, P.; Sasine, J.P. Factors Associated with Post-Chimeric Antigen Receptor T Cytopenias. Encyclopedia. Available online: https://encyclopedia.pub/entry/41508 (accessed on 12 July 2025).
Reinhardt B, Lee P, Sasine JP. Factors Associated with Post-Chimeric Antigen Receptor T Cytopenias. Encyclopedia. Available at: https://encyclopedia.pub/entry/41508. Accessed July 12, 2025.
Reinhardt, Bryanna, Patrick Lee, Joshua P. Sasine. "Factors Associated with Post-Chimeric Antigen Receptor T Cytopenias" Encyclopedia, https://encyclopedia.pub/entry/41508 (accessed July 12, 2025).
Reinhardt, B., Lee, P., & Sasine, J.P. (2023, February 22). Factors Associated with Post-Chimeric Antigen Receptor T Cytopenias. In Encyclopedia. https://encyclopedia.pub/entry/41508
Reinhardt, Bryanna, et al. "Factors Associated with Post-Chimeric Antigen Receptor T Cytopenias." Encyclopedia. Web. 22 February, 2023.
Factors Associated with Post-Chimeric Antigen Receptor T Cytopenias
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This entry is adapted from the peer-reviewed paper 10.3390/cells12040531

Chimeric Antigen Receptor (CAR) T-cell therapy is a promising treatment option for patients suffering from B-cell- and plasma cell-derived hematologic malignancies and is being adapted for the treatment of solid cancers. CAR T is usually associated with cytopenias. These are often biphasic and sometimes prolonged over several months. Cytopenias often lead to infections, need for transfusions of blood products, and increased CAR T morbidity.

CAR T hematopoietic stem cells cytopenia

1. Introduction

Autologous Chimeric Antigen Receptor (CAR) T-cell therapy is approved by the FDA to treat several relapsed or refractory (r/r) hematological malignancies such as Diffuse Large B-Cell Lymphoma (DLBCL), B-cell Acute Lymphoblastic Leukemia (ALL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), and Multiple Myeloma (MM). Much of the enthusiasm for CAR T is supported by the relatively high response rates and durations for these historically difficult-to-treat patient populations. Remarkably, response rates to CAR T-cell therapy in patients with r/r disease are significantly better than alternatives [1], although durability to treatment is varied [2]. For example, typical complete remission (CR) rates to standard immunochemotherapy for r/r diffuse large B-cell lymphoma (DLBCL) can be as low as 7% [3] compared to those for CAR T which reached 58% in the ZUMA-1 trial [4]. In an analysis comparing B-cell lymphoma patient outcomes two years after CAR T or salvage therapy, Sattva et al. found that patients who received axi-cel in the ZUMA-1 trial had a significantly higher ORR and 73% reduced risk of death compared to standard salvage therapy [5]. On the other hand, an average of 60% of patients treated with CAR T for DLBCL experienced disease progression, potentially relating to the composition of the CAR T infusion product and proportion of CAR T regulatory (CAR Treg) cells [2].
Optimizing CAR T efficacy and minimizing toxicity are important next steps to improving patient outcomes and designating CAR T as an earlier phase therapy for patients with hematologic malignancies. In addition to well-characterized CAR T toxicities—such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR T-associated cytopenias (low blood counts)—there are increasingly recognized phenomena that have implications for overall prognosis, CAR T efficacy, and patient experience.
The mechanism driving prolonged CAR T-associated cytopenias is still unknown. The conditioning chemotherapy certainly has an impact; however, it is not a sufficient explanation for the degree of long-term cytopenias in many patients after CAR T. Using the FCR regimen (fludarabine, cyclophosphamide, and rituximab) to treat patients with chronic lymphocytic leukemia (CLL), the rate of prolonged cytopenias in fit patients is only 4.6% [6]. The dose and schedule of fludarabine and cyclophosphamide is like that used in patients with CAR T. Therefore, it is likely that other factors—such as pre-treatment bone marrow health, baseline inflammation, and inflammation driven by CAR T—could contribute to the prolonged cytopenias after CAR T. Other, yet unknown mechanisms are also possible.

2. Factors Associated with Post-CAR T Cytopenias

Not surprisingly, some studies have shown that baseline cytopenias are associated with prolonged cytopenias post CAR T [7]. Many patients receiving CAR T have been heavily pre-treated with cytotoxic chemotherapy which can damage the hematopoietic stem cells and the bone marrow microenvironment durability.
Systemic inflammation driven by increased levels of immune mediators promotes hematopoietic stem cell exhaustion [8] and this inflammation, especially following genotoxic CAR T conditioning treatment, can cause severe and long-lasting cytopenias. This phenomenon can be particularly problematic given the high incidence of inflammatory complications of CAR T-cell therapy.
Pretreatment hematopoietic reserve and inflammatory states appear to be important factors associated with post CAR T-cell cytopenias and their duration. A prolonged cytopenia is defined as an episode of lower-than-normal blood counts that persist for over two weeks to three months without evidence of significant hematopoietic recovery [9]. In a retrospective analysis of 258 patients treated with axi-cel or tisa-cel, pre-treatment low platelet counts, absolute neutrophil count (ANC), and hemoglobin as well as high C-reactive protein (CRP) and ferritin were significantly associated with delayed cytopenias after CAR T [10]. These findings formed the basis of the CAR-HEMATOTOX model, which combines baseline biomarkers (prior to conditioning chemotherapy) into one score that can be used as a guide for predicting patients’ hematopoietic recovery following CAR T. Other studies have also shown that pre-conditioning platelet counts are associated with post-infusion thrombocytopenia [11][12].
In a retrospective analysis of 133 patients with r/r lymphoma receiving CAR T, early cytopenia was associated with peak IL-6, CRP, and ferritin levels as well as incidence and severity of CRS, illustrating that management of baseline inflammation and inflammatory toxicities may decrease incidence and severity of post-infusion cytopenias [11]. In a different analysis of 83 patients treated with axi-cel, tisa-cel, and the CD19-28z CAR T-cell therapy for ALL, within the first week, hemoglobin nadir was 7.1 g/dl, platelets were 29.5 × 103/μL, ANC was 0, and WBC was 0.2 × 103/μL [13]. Recovery of hemoglobin, platelets, neutrophils, and WBC by one year post CAR T therapy was observed in 67%, 78%, 89%, and 89% of patients, respectively. Thus, a significant proportion of patients experienced prolonged cyopenias after treatment. Recovery of cell numbers by one month was significantly associated with baseline cytopenias, as was the CAR construct (tisa-cel was associated with better cell hematopoietic recovery). Increasing grade of CRS or ICANS was negatively associated with hematopoietic recovery, supporting the notion that CAR T-associated inflammation is detrimental to hematopoietic stem/progenitor function.
One potential explanation for the persistent cytopenias post CAR T is emergence of clonal hematopoiesis or myelodysplastic syndrome which may develop after several lines of genotoxic chemotherapy regimens [14]. In the previous study of 83 ALL patients [13], there was only one occurrence of myelodysplasia (MDS) following a patient’s relapse to CAR T, although other studies have reported higher incidences of MDS development [15]. Specifically, in a report of late events in 86 patients following CAR T treatment, 5% developed MDS and 16% experienced prolonged cytopenias [15]. Three of 19 patients in CR who did not have MDS experienced prolonged cytopenias for an average of 18.45 months following CAR T therapy [15]. While the development of MDS post CAR T is associated with cytopenias, the occurrence of prolonged cytopenias is not usually due to MDS. Clonal myeloid disorders are insufficient to explain most CAR T patients with prolonged cytopenias. Rather, cytopenias correlate with additional factors such as pre-lymphodepletion cell numbers and previous lines of therapy [4][16].
Post-infusion cytopenias also increase infection risk, largely due to the decrease in leukocytes available to fight off pathogens. However, repeated transfusion of red blood cells or platelets can increase infection risk as well. Neutropenia may result from a combination of lymphodepleting chemotherapy and immune dysregulation resulting from CRS and ICANS [17]. Multiple studies have correlated severe inflammatory toxicity with infections in ALL and B-Cell Non-Hodgkin Lymphoma patients [17][18]. Additionally, the increased infection risk may be related to age [19], previous infection prior to CAR T [20], the underlying hematologic malignancy [19], severity of CRS and ICANS (which are also risk factors for prolonged cytopenias following CAR T) [13][21].
CAR T-cell therapy can induce prolonged hematologic toxicity (PHT), which is further defined as incidence of grade > 3 neutropenia or thrombocytopenia beyond 29 days following CAR T infusion [22]. Nagle et al. reported that 58% of adult patients with r/r DLBCL treated with CAR-T between 2018 and 2020 developed PHT, which was associated with a 45% decrease in overall survival [22]. Risk factors associated with PHT include CRS, treatment with tocilizumab, administration of steroids, peak ferritin > 5000 ng/mL, and peak CRP > 100 mg/L. Mitigating cytopenias can be a useful first step in preventing the development of PHT.
The severity of CRS and lower pre-conditioning platelet count are predictive of hematologic toxicity in patients receiving CD19 CAR T-cell therapy [12]. In a retrospective analysis of 83 patients receiving axi-cel, tisa-cel, CD19-28z CAR T for B-ALL, or B-cell maturation antigen targeting CAR T for MM, Jain et al. found that the patients who had not progressed or died recovered hemoglobin, platelet, neutrophil, and white blood cell counts [13]. Additionally, increased severity of CRS and ICANS were associated with decreased likelihood of hematopoietic recovery at one month after CAR T [13]. Hematopoietic stem and progenitor cells are vulnerable to systemic inflammation which affects their recovery [8] and inflammation associated with CAR T can damage hematopoietic stem and progenitor cells.
Multiple independent groups have reported evidence of non-CAR T-cells playing a role in prolonged cytopenias. Li et al. [23] used scRNA-sequencing on the bone marrow aspirates from 16 patients with DLBCL treated with axi-cel, in which 11 patients had grade 3–4 cytopenia at day 30 and 5 patients did not; 5 healthy controls were included as comparisons. They found an enrichment of GZMH+ FGFBP2+ CD8 T cells which did not express the CAR within patients with CAR T-associated cytopenias. The most expanded TCR clones were enriched within this population of CD8 T-cells, and these were significantly enriched for interferon (IFN) signaling. IFN gamma can impair self-renewal and differentiation of HSPCs but can be targeted using IFNG-neutralizing antibodies or eltrombopag.
Rejeski et al. [24] found similar results in a single patient with DLBCL treated with tisa-cel. After severe CRS and several episodes of infection, the patient developed prolonged pancytopenia. Using scRNA-sequencing, they also found an oligoclonal population of T cells which did not express the CAR gene but were CD8+ CD57+. The oligoclonal expansion and immunophenotype was strikingly like that seen in aplastic anemia and T-cell large granular lymphocytic leukemia, also associated with pancytopenia [11][12][14][18].
Future studies will clarify the mechanism of CAR T cytopenias with the hope that this will reveal a target for therapeutic intervention. One consistent theme is that inflammation associated with CAR T is one mechanism responsible for prolonged cytopenias.

References

  1. Martino, M.; Alati, C.; Canale, F.A.; Musuraca, G.; Martinelli, G.; Cerchione, C. A Review of Clinical Outcomes of CAR T-Cell Therapies for B-Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2021, 22, 2150.
  2. Haradhvala, N.J.; Leick, M.B.; Maurer, K.; Gohil, S.H.; Larson, R.C.; Yao, N.; Gallagher, K.M.E.; Katsis, K.; Frigault, M.J.; Southard, J.; et al. Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. Nat. Med. 2022, 28, 1848–1859.
  3. Crump, M.; Neelapu, S.S.; Farooq, U.; Van Den Neste, E.; Kuruvilla, J.; Westin, J.; Link, B.K.; Hay, A.; Cerhan, J.R.; Zhu, L.; et al. Outcomes in refractory diffuse large B-cell lymphoma: Results from the international SCHOLAR-1 study. Blood 2017, 130, 1800–1808.
  4. Locke, F.L.; Ghobadi, A.; Jacobson, C.A.; Miklos, D.B.; Lekakis, L.J.; Oluwole, O.O.; Lin, Y.; Braunschweig, I.; Hill, B.T.; Timmerman, J.M.; et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019, 20, 31–42.
  5. Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Reagan, P.M.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; et al. Comparison of 2-year outcomes with CAR T cells (ZUMA-1) vs salvage chemotherapy in refractory large B-cell lymphoma. Blood Adv. 2021, 5, 4149–4155.
  6. Szász, R.; Telek, B.; Illés, Á. Fludarabine-Cyclophosphamide-Rituximab Treatment in Chronic Lymphocytic Leukemia, Focusing on Long Term Cytopenias Before and After the Era of Targeted Therapies. Pathol. Oncol. Res. 2021, 27, 1609742.
  7. Schuster, S.J.; Tam, C.S.; Borchmann, P.; Worel, N.; McGuirk, J.P.; Holte, H.; Waller, E.K.; Jaglowski, S.; Bishop, M.R.; Damon, L.E.; et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021, 22, 1403–1415.
  8. Pietras, E.M. Inflammation: A key regulator of hematopoietic stem cell fate in health and disease. Blood 2017, 130, 1693–1698.
  9. Gill, S.; Carney, D.; Ritchie, D.; Wolf, M.; Westerman, D.; Prince, H.M.; Januszewicz, H.; Seymour, J.F. The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy. Ann. Oncol. 2010, 21, 331–334.
  10. Rejeski, K.; Perez, A.P.; Sesques, P.; Hoster, E.; Berger, C.S.; Jentzsch, L.; Mougiakakos, D.; Frölich, L.; Ackermann, J.; Buecklein, V.; et al. CAR-HEMATOTOX: A model for CAR T-cell–related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood 2021, 138, 2499–2513.
  11. Zhou, J.; Zhang, Y.; Shan, M.; Zong, X.; Geng, H.; Li, J.; Chen, G.; Yu, L.; Xu, Y.; Li, C.; et al. Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma. Front. Immunol. 2022, 13, 997589.
  12. Juluri, K.R.; Wu, Q.V.; Voutsinas, M.J.M.; Hou, J.; Hirayama, A.V.; Mullane, E.; Miles, N.; Maloney, D.G.; Turtle, C.J.; Bar, M.; et al. Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy. Blood Adv. 2022, 6, 2055–2068.
  13. Jain, T.; Knezevic, A.; Pennisi, M.; Chen, Y.; Ruiz, J.D.; Purdon, T.J.; Devlin, S.M.; Smith, M.; Shah, G.L.; Halton, E.; et al. Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies. Blood Adv. 2020, 4, 3776–3787.
  14. Taneja, A.; Jain, T. CAR-T-OPENIA: Chimeric antigen receptor T-cell therapy-associated cytopenias. EJHaem 2022, 3, 32–38.
  15. Cordeiro, A.; Bezerra, E.D.; Hirayama, A.V.; Hill, J.A.; Wu, Q.V.; Voutsinas, J.; Sorror, M.L.; Turtle, C.J.; Maloney, D.G.; Bar, M. Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. Biol. Blood Marrow Transplant. 2020, 26, 26–33.
  16. Kochenderfer, J.N.; Somerville, R.P.; Lu, T.; Yang, J.C.; Sherry, R.M.; Feldman, S.A.; McIntyre, L.; Bot, A.; Rossi, J.; Lam, N.; et al. Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy. Mol. Ther. 2017, 25, 2245–2253.
  17. Hill, J.; Li, D.; Hay, K.; Green, M.L.; Cherian, S.; Chen, X.; Riddell, S.R.; Maloney, D.G.; Boeckh, M.; Turtle, C.J. Infectious complications of CD19-targeted chimeric antigen receptor–modified T-cell immunotherapy. Blood 2018, 131, 121–130.
  18. Logue, J.M.; Zucchetti, E.; Bachmeier, C.A.; Krivenko, G.S.; Larson, V.; Ninh, D.; Grillo, G.; Cao, B.; Kim, J.; Chavez, J.C.; et al. Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. Haematologica 2021, 106, 978–986.
  19. Dayagi, T.W.; Sherman, G.; Bielorai, B.; Adam, E.; Besser, M.J.; Shimoni, A.; Nagler, A.; Toren, A.; Jacoby, E.; Avigdor, A. Characteristics and risk factors of infections following CD28-based CD19 CAR-T cells. Leuk. Lymphoma 2021, 62, 1692–1701.
  20. Wudhikarn, K.; Perales, M.-A. Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy. Bone Marrow Transplant. 2022, 57, 1477–1488.
  21. Faramand, R.G.; Davila, M.L. CAR T-cell hematotoxicity: Is inflammation the key? Blood 2021, 138, 2447–2448.
  22. Nagle, S.J.; Murphree, C.; Raess, P.W.; Schachter, L.; Chen, A.; Hayes-Lattin, B.; Nemecek, E.; Maziarz, R.T. Prolonged hematologic toxicity following treatment with chimeric antigen receptor T cells in patients with hematologic malignancies. Am. J. Hematol. 2021, 96, 455–461.
  23. Li, X.; Deng, Q.; Henderson, J.; Watson, G.; Deaton, L.; Cain, T.; Fayad, L.; Iyer, S.P.; Hagemeister, F.B.; Nastoupil, L.J.; et al. Targetable Cellular Etiology of Prolonged Cytopenia Following CD19 CAR T-Cell Therapy. Blood 2022, 140, 4502–4503.
  24. Rejeski, K.; Wu, Z.; Blumenberg, V.; Kunz, W.G.; Mueller, S.; Kajigaya, S.; Gao, S.; Bücklein, V.L.; Frölich, L.; Schmidt, C.; et al. Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL. Blood 2022, 140, 2175–2179.
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Subjects: Hematology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Bryanna Reinhardt
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Patrick Lee
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Joshua P. Sasine
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Update Date: 24 Feb 2023
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