Use of Eltrombopag to Improve Thrombocytopenia and Tranfusion Requirement in Anti-CD19 CAR-T Cell-Treated Patients

Abstract

Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 10⁹/L (Rho = 0.639, p < 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients.

Keywords: CAR-T; adverse events; eltrombopag; neutropenia; pan-cytopenia; platelet transfusion; red blood cell transfusion; thrombocytopenia; thrombopoietin receptor agonist.

Figure 1

Flowchart diagram of the study and patients finally enrolled. DP, disease progression; ELT, eltrombopag; LD, lymphodepletion; mo, months; PLT, platelets.

Figure 2

Cytopenia recovery subsequent to treatment with eltrombopag (A) The number of patients who recovered PLT/RBC transfusion independence or recovered from ANC < 0.5 × 10⁶/L, together with the total number of patients who required PLT/RBC transfusion or presented with ANC < 0.5 × 10⁶/L before the start of eltrombopag are indicated above each histogram (left). The number of patients who achieved simultaneously either platelet/RBC transfusion independence and ANC ≥ 0.5 × 10⁶/L or recovery from the three severe cytopenias upon eltrombopag treatment is also indicated (right). (B) The same calculations are presented after stratifying patients according to the type of CAR-T cell used. ANC, absolute neutrophil counts; axi-cel, axicabtagene ciloleucel; Hgb, hemoglobin; PLT, platelets; RBC, red blood cells; tisa-cel, tisagenlecleucel.

Figure 3

Median time elapsed in each one of the phases of the study. The median number of days was considered for each leg. The number of patients submitted to BT and LD, the number (percent) of patients who developed PLT transfusion dependence (above), severe neutropenia (middle), or RBC transfusion dependence (below), and the number (percent) of patients who achieved or did not achieve recovery before the end of the study are indicated. * Only those patients who developed platelet transfusion dependence (above), severe neutropenia (ANC < 0.5 × 10⁶/L, middle), or RBC transfusion dependence (below) were considered. ^† Only those patients who achieved platelet transfusion independence (above), reached ANC levels ≥ 0.5 × 10⁶/L (middle), or achieved RBC transfusion independence (below) were considered. ^‡ Only those patients who did not recover from platelet transfusion requirement (above), ANC drop to levels < 0.5 × 10⁶/L (middle) or RBC transfusion requirement (below) were considered. ANC, absolute neutrophil counts; BT, bridging chemotherapy; LD, lymphodepleting chemotherapy; PLT, platelets; RBC, red blood cells.

Figure 4

Time course of platelet count recovery with eltrombopag. Patients who presented with platelet counts < 20 × 10⁹/L after CAR-T cell therapy and started treatment with eltrombopag were considered. Kaplan-Meier curves were constructed considering the time elapsed between the first administration of eltrombopag and the recovery of platelet counts either ≥20 × 10⁹/L (blue line, n = 29) or ≥50 × 10⁹/L (red line, n = 26). Tick marks indicate those patients whose data were censored at the last follow-up date, either because of exitus or loss to follow-up, without having achieved PLT counts ≥ 20 × 10⁹/L (blue, n = 9) or >50 × 10⁹/L (red, n = 12). ELT, eltrombopag; PLT, platelets.

Figure 5

Correlation between total transfused platelet units and time between the start of eltrombopag and platelet transfusion independence achievement. The correlation between the total amount of transfused platelet units and the time elapsed between the start of eltrombopag therapy and the achievement of platelet transfusion independence is shown (n = 29). The one-tailed Rho Spearman test was used. ELT, eltrombopag; PLT, platelets.

Figure 6

PLT transfusion requirement according to response to eltrombopag. (A) The amount of platelet units used in the patients who achieved platelet transfusion independence while in treatment with eltrombopag (responders) was compared against the platelet units used in those who had not achieved transfusion independence by the end of follow-up (non-responders). (B) The same comparison was performed within the group of responders, between those who achieved transfusion independence earlier (early responders) or later (late responders) than 30 days after the first dose of eltrombopag was administered. The one-tailed Mann-Whitney U test was used for comparisons. PLT, platelets.

Figure 7

Transfusional requirement according to CAR-T cell type. The amount of platelet units (A) or RBC units (B) used in the patients who achieved platelet or RBC transfusion independence, respectively, is shown after categorizing them according to CAR-T cell type. The one-tailed Mann-Whitney U test was used for comparisons. Axi-cel, axicabtagene ciloleucel; PLT, platelets; RBC, red blood cells; tisa-cel, tisagenlecleucel.