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Cytopenias are the most common adverse event occurring across a range of hematologic tumors in patients receiving chimeric antigen receptor (CAR) T-cell therapy.1 Cytopenias are associated with increased morbidity and mortality, risk of infections, and bleeding complications. They may also lead to additional disease sequelae, including poor quality of life and increased use of healthcare resources. Various etiologies are associated with cytopenias, some of which are not well understood, which presents challenges and uncertainties around the management.1
During the International Myeloma Society (IMS) 4th Immune Effector Cell Therapies in Multiple Myeloma Workshop, Lin1 presented a session on the real-world considerations for commercial CAR T-cell therapies, including the etiologies and management of cytopenias.1 In the presentation, Lin discusses an article published in Blood by Jain et al.2 on the management of cytopenias post CAR T‑cell infusion. Here, we summarize the potential etiologies and key recommendations for the management of cytopenias.
Cytopenia may be caused by several underlying pathophysiological mechanisms and can be classified into three types by considering the timeline from CAR T-cell infusion. Figure 1 shows the potential underlying etiologies and recommended management strategies proposed by Jain et al.2
Figure 1. Etiologies and recommended management strategies of cytopenia*
ANC, absolute neutrophil count; CAR, chimeric antigen receptor; G-CSF, granulocyte colony stimulating factor; IEC-HS, hemophagocytic lymphohistiocytosis-like hyperinflammatory syndrome associated with immune effector cells; LD, lymphodepletion; LGL, larger granular lymphocytosis; NGS, next-generation sequencing; PJP; Pneumocystis jirovecii pneumonia; TA-TMA, transplant-associated thrombotic microangiopathy; TPO, thrombopoietin.
*Adapted from Jain, et al.2
†Anti-viral prophylaxis initiated early post CAR T-cell infusion and continued for 6–12 months; anti-PJP prophylaxis initiated at Day ~28 until CD4+ cell count >200/mm3; if ANIC <500/mm3 by day 7–10, consider administering G-CSF.
‡Rapidly rising ferritin, fever, organ dysfunction.
‖Consider anakinra, steroids, ruxolitinib.
Most cases of early cytopenia occur as a result of CAR T-cell expansion in vivo by lymphodepletion (LD) chemotherapy, inducing a lymphopenic environment. This increases homeostatic cytokines and decreases the suppressive cells. Although LD is not myeloablative, and recovery of blood count is expected following chemotherapy, cytopenias may continue or persist beyond those associated with LD alone. Cytopenia can be biphasic, with patients experiencing a second occurrence of reduced absolute neutrophil count (ANC) between Week 3 and Month 1, termed as intermittent neutrophil recovery. This is also observed in many patients with prolonged cytopenia after CAR T-cell infusion. A small proportion of patients may present with suboptimal count recovery post-nadir that is less responsive to growth factors. In these patients, late cytopenia is common and a full recovery may not occur until months later.
Prolonged and late (>90 days) cytopenia after CAR T‑cell infusion may be caused by immune-driven suppression of hematopoietic stem cells and marrow microenvironment changes. Prolonged cytopenia is associated with preceding cytopenia, either disease- or chemotherapy-related, at the time of CAR T‑cell infusion. Marrow reserves at the time of CAR T‑cell infusion may also increase the probability of developing prolonged cytopenia. Patients undergoing allogeneic bone marrow transplantation (BMT) with decreased marrow are susceptible to prolonged cytopenia. Residual or recurrent disease in the marrow, high marrow disease, and the co-stimulatory domain of the CAR may lead to prolonged cytopenia.
Infections and immune effector cell-associated hemophagocytic lymphistiocytosis-like syndrome (IEC-HS) should be considered in both early and prolonged cytopenia. IEC-HS should also be monitored in patients with previously resolved CRS followed by a rapid increase in ferritin (>10,000 mg/mL), recurrence of fever, and new onset of severe cytopenia.
The following biomarkers that are consistent across both early and prolonged cytopenia should be considered:
The most likely trajectory for patients with prolonged or late cytopenia in the absence of additional pathophysiological causes is gradual recovery. These patients should be monitored for active primary disease in the marrow or secondary myeloid malignancies. With regards to patients with prolonged cytopenia, the following should be considered:
Late cytopenias are associated with a hypoplastic marrow without evidence of fibrosis, dysplasia, or clonal hematopoiesis of indeterminate potential (CHIP). Persistent CAR activation may cause immune-mediated mature blood cell destruction, leading to late cytopenia accompanied by severe trilineage aplasia.
Paucity of data in the management of prolonged or late transfusion-dependent multi-lineage cytopenias creates a challenge in their management. Although hematopoietic stem cell boost is recommended, this strategy is only feasible if stem cells from previous autologous or an allogeneic BMT have been preserved. However, as stem cell products may be contaminated with primary malignant cells, caution should be taken while considering this option.
Cytopenias vary in etiology and non-CAR T-cell infusion causes should be considered when assessing patients. Cytopenias may be associated with severity of inflammatory toxicities, pre-existing cytopenias, previous BMT, and marrow disease. However, further investigations into the underlying mechanism of cytopenias will inform future treatment strategies. Currently, cytopenia should be managed based on its severity and timing post CAR T-cell infusion.
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