Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies

Abstract

Factors contributing to hematopoietic recovery following chimeric antigen receptor (CAR) T-cell therapy have not been well studied. In an analysis of 83 patients with hematologic malignancies treated with CAR T-cell therapy, we describe patterns of hematopoietic recovery and evaluate potentially associated factors. We included patients who received axicabtagene ciloleucel (n = 30) or tisagenlecleucel (n = 10) for B-cell lymphoma, CD19-28z CAR T therapy for B-cell acute lymphoblastic leukemia (NCT01044069; n = 37), or B-cell maturation antigen targeting CAR T cells for multiple myeloma (NCT03070327; n = 6). Patients treated with CAR T cells who had not progressed, died, or received additional chemotherapy had “recovered” (per definition in Materials and methods section) hemoglobin, platelet, neutrophil, and white blood cell counts at rates of 61%, 51%, 33%, and 28% at month 1 postinfusion and 93%, 90%, 80%, and 59% at month 3 postinfusion, respectively. Univariate analysis showed that increasing grade of immune effector cell–associated neurological syndrome (ICANS), baseline cytopenias, CAR construct, and higher peak C-reactive protein or ferritin levels were statistically significantly associated with a lower likelihood of complete count recovery at 1 month; a similar trend was seen for cytokine release syndrome (CRS). After adjustment for baseline cytopenia and CAR construct, grade ≥3 CRS or ICANS remained significantly associated with the absence of complete count recovery at 1 month. Higher levels of vascular endothelial growth factor and macrophage-derived chemokines, although not statistically significant, were seen patients without complete count recovery at 1 month. This remains to be studied further in larger prospective studies.

Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies

“…In MM patients, with BCMA being the most commonly used target antigen, clinical data on CAR T cell-related toxicity are mainly based on these studies. The most common toxicities include cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and cytopenia-related complications, which have also been reported in studies investigating anti-CD19 CAR T cell therapy in B cell leukemia and/or non-Hodgkin's lymphoma (NHL) (21,(72)(73)(74)(75)(76). However, severe CRS and/or ICANS are less common in MM than that in ALL or NHL, probably due to reduced T cell fitness in these heavily pretreated patients with RRMM.…”

“…CAR T cell therapy is often associated with a prolonged cytopenia phase and excessive cytokine production (71,72). In general, the severity of CAR T cell therapy associated toxicity is related to tumor burden, dose of CAR T cells, as well as the antigen that has been targeted.…”

Emerging immunotherapies in multiple myeloma

“…Neurotoxicity was reported in less than 20% of patients with severe neurotoxicity (≥grade 3) in less than 7% of patients. Another common side effect is cytopenia, which has also been thought to be secondary to the lymphodepleting chemotherapy, ongoing CAR T cell activity, and disruption of hematopoiesis showing severe hypocellularity in the bone marrow, but most patients recover with time 120121…”

Hematologic Rescue of CAR T-cell–mediated Prolonged Pancytopenia Using Autologous Peripheral Blood Hematopoietic Stem Cells in a Lymphoma Patient

“… 2 However, the analysis of multiple proinflammatory cytokines and chemokines as well as growth factors yielded no significant differences between the 8 patients with complete recovery at 1 month post-CART therapy besides macrophage-derived CCL22. 7 Preexisting bone marrow damage seems to represent a risk factor for sustained myelosuppression after CART therapy as preexisting thrombocytopenia was associated with prolonged cytopenia and 2 of 8 patients showed signs of myelodysplasia in 1 study. 3 Moreover, prior autologous or allogenic stem cell transplantation correlated with delayed recovery.…”

“…In a cohort of 41 patients suffering from lymphoma, leukemia, and myeloma, correlation of CRS and high inflammatory parameters still remained significant after adjustment for other factors that cause prolonged cytopenia (ie, baseline cytopenia, CAR construct). 7 Thus, perturbations of cytokines and inflammation are 1 possible explanation. Reduced levels of stromal cell-derived factor 1, a CXCR4 ligand that regulates hematopoietic stem cell migration and survival, neutrophil migration, and pro-pre-B cell development were implicated in delayed neutrophil recovery in 1 study.…”