Peer Reviewed
This review explores cytopenia after CAR T-cell therapy, including its risk stratification and management with growth factors, thrombopoietin-receptor agonists, and hematopoietic stem cell boosts.
Précis
This review explores cytopenia after CAR T-cell therapy, including its risk stratification and management with growth factors, thrombopoietin-receptor agonists, and hematopoietic stem cell boosts.
Introduction
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Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory hematologic malignancies, offering high response rates and durable remissions. However, these benefits come with a distinct toxicity profile that presents significant management challenges.1 Although the extensive study of potentially life-threatening toxicities, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome, has informed the iterative development of effective risk evaluation and mitigation strategies over the years, similar advancements have not been achieved for hematological toxicities. Despite the wealth of pivotal trials and real-world data highlighting the significance of cytopenia following CAR T-cell therapy, this area remains relatively unexplored.2 Recently, the European Hematology Association (EHA) and European Society for Blood and Marrow Transplantation (EBMT) jointly developed consensus recommendations for defining and grading immune effector cell–associated hematotoxicity (ICAHT); however, significant practice variation still occurs.1
Cytopenia, which affects 1 or more cell lineages, is the most frequent condition listed in the Common Terminology Criteria for Adverse Events of grade 3 or greater associated with CAR T-cell therapy.1-3 Although the underlying pathophysiology remains to be fully elucidated, cytopenia appears to be a class effect of CAR T-cell therapy, independent of the target antigen or disease entity.3 Furthermore, this effect is characterized by profound and persistent cytopenia, often spanning months to years after CAR T-cell infusion, with periods of intermittent count recovery.4 Associated clinical sequelae, such as severe infectious diseases and bleeding complications, drive morbidity and nonrelapse mortality, resulting in significant impacts on both the patient and the health care system.1,2,4
Current definitions for cytopenia post CAR T-cell therapy are heterogeneous and arbitrary, with most systems classifying according to the time from CAR T-cell infusion. Table 1 shows the EHA/EBMT consensus recommendations for defining and grading ICAHT.1 Given the rarity of isolated occurrences of thrombocytopenia or anemia and the clinical significance of neutropenia following CAR T-cell therapy, ICAHT severity is guided by the depth and duration of neutropenia, as shown in Table 1.1
ANC, absolute neutrophil count; ICAHT, immune effector cell–associated hematotoxicity.
aMeasured ≥ 2 time points, or nontransient neutropenia.
Several risk factors contribute to the development of cytopenia post CAR T-cell therapy; however, this area remains incompletely understood.2,3,5 EHA/EBMT recommendations consider previous history of hematopoietic stem cell transplantation (HSCT), baseline cytopenia, high tumor burden, systemic inflammation, and presence of bone marrow infiltration as high-risk features for developing ICAHT.1
CAR-HEMATOTOX is a predictive model developed to identify individuals at risk of hematotoxicity post CAR T-cell therapy (Figure).4 It has been retrospectively validated in lymphoma and multiple myeloma populations. The model incorporates 5 key markers associated with hematopoietic reserve and baseline systemic inflammation: platelet count, absolute neutrophil count, hemoglobin, C-reactive protein, and ferritin. These markers are assessed before starting lymphodepletion chemotherapy to determine a score that distinguishes between low-risk (score, 0 or 1) and high-risk (score, ≥ 2) individuals. High-risk scores correlate with a longer duration of neutropenia and a higher incidence of severe thrombocytopenia and anemia. Furthermore, high-risk scores are independently associated with an increased probability of severe infection, with an adjusted OR of 7.7 (95% CI, 3.4-17.3).5 Additionally, when compared with low-risk scores, high-risk scores are associated with inferior progression-free survival and overall survival, with statistically significant HRs of 1.8 (95% CI, 1.3-2.5) and 2.6 (95% CI, 1.7-3.9), respectively.5 Although the model helps identify individuals at risk, its negative predictive value implies that not all high-risk patients will necessarily develop severe hematotoxicity. Nevertheless, the model can potentially assist in risk stratification, anticipate patient needs and resource allocation, and guide toxicity management. Further study, including independent and prospective validation, is required.4
ANC, absolute neutrophil count; CRP, C-reactive protein; HT, hematotoxicity; LBCL, large B-cell lymphoma; MCL, mantle cell lymphoma; MM, multiple myeloma.
The management of cytopenia post CAR T-cell therapy is primarily supportive and includes packed red blood cell (PRBC) and/or platelet transfusions, granulocyte colony-stimulating factor (G-CSF), thrombopoietin receptor agonists (TPO-RA), and hematopoietic stem cell boost (HSCB).1,2 These management strategies have been described in retrospective analyses, and the outcomes are summarized in Table 2. Additionally, appropriate anti-infective prophylaxis is crucial for this patient population and generally aligns with recommendations for HSCT. Best practice guidelines for managing cytopenia post CAR T-cell therapy have recently been published by EHA/EBMT.1
AEs, adverse events; axi-cel, axicabtagene ciloleucel; brexu-cel, brexucabtagene autoleucel; CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; CRS, cytokine release syndrome; G-CSF, granulocyte colony-stimulating factor; HSCB, hematopoietic stem cell boost; ICANS, immune effector cell–associated neurotoxicity syndrome; ide-cel, idecabtagene vicleucel; IV, intravenous; liso-cel, lisocabtagene maraleucel; MDS, myelodysplastic syndrome; tisa-cel, tisagenlecleucel.
Transfusions, including PRBC and platelets, are an essential part of supportive care post CAR T-cell therapy. The EHA/EBMT recommend following existing institutional guidelines with transfusions for anemia and thrombocytopenia.1 There is limited experience in or literature describing the use of erythropoietic stimulating agents for anemia post CAR T-cell therapy; its use is not recommended at this time.6
Initially, there was hesitancy regarding the use of G-CSF following CAR T-cell therapy due to concerns about promoting proinflammatory cytokine secretion, which could exacerbate acute CAR T-cell–related immunotoxicity. However, multiple studies have failed to demonstrate this association, even with administration as early as day +2 post infusion.7-10 G-CSF appears to be safe and may lead to transient responses, offering benefits such as shorter duration of neutropenia, reduced hospitalization, and decreased need for intravenous antibiotics. However, these benefits have not consistently correlated with a decrease in infections.11,12 EHA/EBMT recommend a risk-stratified approach. For individuals at high risk of ICAHT, G-CSF prophylaxis should be considered from day +2 post infusion to shorten the expected length of severe neutropenia. For those at low risk, therapeutic G-CSF (filgrastim 5 mcg/kg rounded to the nearest vial size) daily until count recovery is recommended around day +7 to day +21, provided the patient is neutropenic and without ongoing CRS. If a response is not observed, the dose may be increased to 10 mcg/kg. More than 80% of patients receiving CAR T-cell therapy ultimately respond to growth factor support. However, repeated courses of therapeutic G-CSF may be required due to the phasic trajectory of count recovery. Lack of response would be an indication for bone marrow biopsy and consideration of G-CSF discontinuation.1,2
TPO plays a critical role in hematopoiesis and platelet production and is expressed on hematopoietic stem cells. TPO RAs, such as eltrombopag (Promacta; Novartis Pharmaceuticals Corporation) and romiplostim (Nplate; Amgen Ltd), have been investigated in post CAR T-cell therapy in 3 retrospective studies.13-15 Although the data are limited, TPO-RAs have demonstrated safety and potential efficacy in achieving independence from platelet transfusions and resolution of thrombocytopenia within approximately 1 to 2 months after initiation.13-15 According to EHA/EBMT recommendations, the use of TPO-RAs following CAR T-cell therapy should parallel the practice for HSCT.1 Specifically, patients who remain transfusion dependent beyond day +30 after CAR T-cell infusion should be initiated on a TPO-RA, such as eltrombopag 75 mg daily, and increased to a target dose of 150 mg daily after 1 week. Additionally, based on current data, it is reasonable to consider tapering the dose in patients who do not achieve a response within 2 months of TPO-RA initiation.13-15
The concept of HSCB has long been utilized in transplantation to restore hematopoiesis.1 This approach can also be applied to patients experiencing persistent or life-threatening cytopenia after CAR T-cell therapy, provided the patient has a source of stored stem cells, typically from a previous transplant. Three small, retrospective studies have explored the safety and feasibility of HSCBs after CAR T-cell therapy. Overall, HSCBs appear to be highly efficacious, with a majority of patients experiencing a sustained response in neutrophils and platelets within 2 to 3 weeks, and no AEs have been noted. However, there is wide variability in the timing of the boost and the cell dose.16-18 In a subgroup analysis, Gagelmann et al found that the timing from CAR T-cell infusion to HSCB and the subsequent response were significantly correlated. An early HSCB (within 43 days) was associated with an earlier and more stable response. However, it is important to note that 4 of the 5 patients who received an HSCB for neutropenia with an active infection did not demonstrate a response.18 Although HSCBs appear to be a safe and effective method for restoring trilineage hematopoiesis, the optimal timing and cell dose remain unclear. EHA/EBMT recommend using an HSCB for grade 3 or greater ICAHT beyond day +14 provided a boost is readily available and G-CSF refractoriness has been established. However, prophylactic stem cell collection in high-risk candidates is generally not accepted, given the additional logistical, financial, and resource utilization considerations it may add to the already complex process of CAR T-cell therapy.1
Summary
Mary McGann, PharmD, BCOP, is a pharmacy clinical specialist (BMT/cell therapy) in the Department of Pharmacy, Medical niversity of South Carolina, Charleston.
Brijesh Gautama, MPharm (Hons), MSc, PGDip, is a lead pharmacist (advanced therapy medicinal products and genomic medicine), in the Department of Pharmacy, University Hospitals Bristol and Weston NHS Foundation Trust in Bristol, England.
In summary, cytopenia following CAR T-cell therapy is common and has a significant impact on both patients and the health care system. Although the CARHEMATOTOX model can help identify those at risk, it requires prospective validation to optimize its utilization and impact. Various strategies, including growth factor support, TPO-RAs, and HSCBs, have been employed to manage cytopenia after CAR T-cell therapy, and they appear to be safe and potentially efficacious. However, the ideal timing and dosing of these interventions remain uncertain. Furthermore, it is important to recognize the limitations of the current retrospective evidence base and acknowledge that some instances of cytopenia may resolve over time without specific intervention. To gain a better understanding, further prospective, randomized, and controlled studies are warranted to determine the most effective management strategies for cytopenia following CAR T-cell therapy.
References
The authors have nothing to disclose.
