Emerging Approaches for CAR T-Cell Cytopenias

Chimeric antigen receptor T-cell therapy (CAR T) has emerged as a breakthrough approach in the treatment of certain B-cell hematologic malignancies, leading to improved survival outcomes in heavily pretreated patients.^1-6 Nevertheless, its clinical benefit is counterbalanced by a spectrum of therapy-related toxicities. The most extensively characterized of these are the cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), conditions treated with corticosteroids and the IL-6 receptor antagonist tocilizumab (Actemra). Beyond these well-established toxicities, growing clinical evidence highlights the occurrence of noncanonical complications. These include prolonged cytopenias, recently termed immune effector cell–associated hematologic toxicity (ICAHT), and immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), both of which can present substantial challenges during postinfusion care.

Here, the focus is on ICAHT and IEC-HS, offering a practical algorithmic framework to support diagnostic and therapeutic decision-making in clinical practice (FIGURE).

Assessing Cytopenia Post CAR T

Cytopenia following CAR T-cell therapy is a clinically significant complication, as it exposes the patients who are immunocompromised to a high risk of severe infections and recurrent hospitalization.⁷

According to expert consensus, early ICAHT denotes cytopenias occurring within the first month after CAR T-cell infusion, usually driven by lymphodepleting chemotherapy, and late ICAHT is defined as cytopenia persisting or arising beyond day 30 from infusion. Early ICAHT (days 0-30) is graded by both depth and duration of neutropenia, whereas late ICAHT (after day +30) is classified solely by severity (grade 1-4) according to neutropenia depth.⁷

The risk of onset of ICAHT is influenced by a complex interplay of disease-specific features, prior therapeutic exposures, baseline bone marrow reserve, systemic inflammatory markers, CAR T construct characteristics, and postinfusion events.

Neutrophil recovery after CAR T infusion exhibits 3 reproducible patterns: the rapid “quick” recovery form (~40% of patients), a biphasic “intermittent” course (~40%), and the “aplastic” phenotype (~20%), which is associated with persistent cytopenia, refractoriness to granulocyte colony-stimulating factor (G-CSF), and high morbidity and mortality.⁸ To refine the risk assessment, the CAR-HEMATOTOX score has been established as a validated tool that can predict prolonged neutropenia and, in particular, the development of the aplastic phenotype. CAR-HEMATOTOX integrates hematopoietic reserve (absolute neutrophil count [ANC], hemoglobin, and platelet count) and baseline inflammatory status (C-reactive protein, ferritin). The model was validated against the end point of severe neutropenia (ANC <500/μL for ≥14 days within 60 days after CAR T infusion). This score is characterized by high sensitivity but lower specificity, meaning that it presents a lower positive predictive value—not all high-risk patients develop hematotoxicity and high negative predictive value—effective in ruling out severe hematotoxicity in low-risk patients. The score allows early identification, prior to lymphodepleting chemotherapy, of patients at high risk of developing post-CAR T cytopenia (score 2-7). In these patients, prophylactic G-CSF is recommended starting from day 2, and infectious prophylaxis should also be considered.⁹

In a patient with cytopenia post CAR T, the diagnostic stepwise approach includes^7-9:

1. Initial evaluation (beyond 2 to 3 weeks post infusion):

• Rule out drug-induced cytopenia
• Assessment for vitamin deficiencies (vitamin B₁₂, folic acid)
• Investigate infectious causes (bacterial, fungal, or viral infections—cytomegalovirus, Epstein-Barr virus, parvovirus B19, hepatitis, HIV)
• Consider sustained inflammatory stressors (CRS/macrophage activation syndrome [MAS] or IEC-HS)
• Exclude relapse or active bone marrow disease

2. Advanced evaluation (conduct if step 1 is inconclusive, in grade 3 or higher ICAHT, or G-CSF refractoriness [no count recovery despite 5 days or more of G-CSF support] and beyond day 14 after CAR T infusion)

• Viral studies in polymerase chain reaction (human herpes virus 6, John Cunningham virus, Epstein-Barr virus, adenovirus, herpes simplex virus)
• Bone marrow aspiration and biopsy followed by cytogenetics and next-generation sequencing (reserved for cases of profound, prolonged marrow aplasia to exclude secondary myeloid malignancies or relapse)

Treatment of cytopenia post-CAR T with transfusions

Transfusions (red blood cells, platelets) are an essential part of supportive care.

Irradiation of blood products is recommended¹⁰:

• From 7 days before leukapheresis
• Until at least 90 days after CAR T-cell infusion
• Longer if conditioning, disease status, or prior treatments indicate

G-CSF

During the first experience of CAR T-cell infusion, G-CSF use was initially avoided due to concerns of worsening CRS or ICANS. Recent studies, however, have shown that prophylactic or early G-CSF (eg, day +2) accelerates neutrophil recovery, reduces febrile neutropenia, and does not increase high-grade CRS or ICANS.^11,12 Current evidence supports early G-CSF in high-risk patients with anticipated prolonged neutropenia, whereas therapeutic G-CSF remains appropriate for non–high-risk patients with ANC less than 500/μL. Lack of response may indicate an aplastic recovery phenotype, whereas most patients (>80%) achieve count recovery with growth factor support. Recurrent neutropenia may necessitate intermittent readministration.

Thrombopoietin Receptor Agonists (TPO)

TPO (eltrombopag [Promacta], romiplostim [Nplate]) may be considered in patients with prolonged or late thrombocytopenia following CAR T, typically emerging in the second month postinfusion.¹³ Evidence supporting their use in this setting is scarce and limited to small single-center case series. Reported benefits include improvement in platelet counts, hemoglobin, and ANC, with some patients achieving transfusion independence. Given the paucity of data, their use should follow practices established after allogeneic hematopoietic cell transplantation (allo-HCT) and may be considered in G-CSF-refractory cases.

Infection Prophylaxis

Post-CAR T infection prophylaxis should follow European Hematology Association/European Society for Blood and Marrow Transplantation recommendations: antiviral and Pneumocystis carinii prophylaxis, plus intravenous immunoglobulin in cases of severe hypogammaglobulinemia.⁹

Antibacterial prophylaxis is risk-adapted, based on CAR-HEMATOTOX score, degree of neutropenia, and local epidemiology. Fluoroquinolone prophylaxis is advised in high-risk patients with ANC less than 500/µL.

Antifungal prophylaxis (micafungin or posaconazole) is recommended for grade 3 neutropenia, prior allogeneic transplant, history of aspergillosis, or prolonged corticosteroid use.

Hematopoietic Cell Boost and Allogeneic Hematopoietic Cell Transplantation (allo-HCT)

Patients refractory to G-CSF beyond day 14 post CAR T are at high risk for severe infections and require alternative strategies. Options include TPO agonists (especially with concomitant thrombocytopenia), anti-inflammatory therapies in the setting of CRS/ICANS, and hematopoietic stem cell boosts when available. Early application of CD34+ cell boosts appears feasible and associated with improved outcomes, although availability and logistical constraints limit routine use.¹⁴ Prophylactic collection remains investigational and warrants further study.

For grade 4 ICAHT persisting beyond day 30, the panel advises considering allo-HCT as a last-resort option. The decision must balance risks, potential for spontaneous recovery, and patient goals, with months 3 to 6 post CAR T considered a reasonable window.¹⁵ If allo-HCT is pursued, donor selection, conditioning, and immunosuppression require individualized discussion, given the paucity of evidence.

IEC-HS

Classical definitions of secondary hemophagocytic lymphohistiocytosis (HLH) share diagnostic criteria with CRS, making differentiation challenging, particularly given the overlap with macrophage activation syndrome.¹⁶ To distinguish a specific CAR T–related entity, experts introduced the term IEC-HS, with corresponding severity grading and management guidelines. The American Society for Transplantation and Cellular Therapy panel defines IEC-HS as a hyperinflammatory syndrome distinct from CRS and ICANS, presenting with HLH-like features, cytopenias, hyperferritinemia, coagulopathy, and/or transaminitis. Diagnosis requires elevated or rapidly rising ferritin, while recurrent CRS must remain in the differential.¹⁷ Prompt recognition and exclusion of infection or malignancy are essential. First-line treatment is anakinra (Kineret), alone or with corticosteroids; if unresponsive within 48 hours, ruxolitinib (Jakafi), emapalumab (Gamifant), or low-dose etoposide may be considered.

Recognition of noncanonical hematologic toxicities after CAR T therapy has advanced considerably, with ICAHT and IEC-HS now recognized as distinct clinical entities. The establishment of standardized diagnostic and severity criteria provides a foundation for harmonized reporting, improved mechanistic understanding, and evidence-based management. Moreover, the feasibility of prophylactic strategies, such as stem cell collection in high-risk patients, warrants careful evaluation to balance clinical benefit against logistical and economic costs. Ultimately, ongoing refinement of monitoring and therapeutic approaches will be key to optimizing safety and outcomes in an expanding landscape of immune effector cell therapies.

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