Multinational retrospective analysis of bridging therapy prior to chimeric antigen receptor t cells for relapsed/refractory acute lymphoblastic leukemia in children and young adults

Abstract

Anti-CD19 chimeric antigen receptor T cells (CAR) are a well-established treatment option for children and young adults suffering from relapsed/refractory B-lineage acute lymphoblastic leukemia. Bridging therapy is used to control disease prior to start of lymphodepletion before CAR infusion and thereby improve efficacy of CAR therapy. However, the effect of different bridging strategies on outcome, side effects and response to CAR therapy is still poorly understood. In this retrospective, multinational study, real-world data were collected from 14 different sites in Germany, Austria and Switzerland on 88 patients receiving 93 2nd-generation CAR therapies. Bridging therapy was classified into the categories 1) no systemic therapy (15/93 treatments), 2) low-intensity therapy (38/93 treatments) and 3) high-intensity therapy (39/93 treatments). We analyzed the impact of bridging regimens on clinical outcome. Patients receiving a high-intensity bridging therapy had a significantly higher tumor burden at time of eligibility compared to patients treated with a low-intensity or no systemic bridging therapy. They suffered significantly more from bacterial adverse events and mucositis. Overall survival was significantly better for patients who did not receive any bridging therapy in comparison to patients who had been treated with a low- or high-intensity bridging regimen. In conclusion, in this retrospective cohort, high-intensity bridging therapy has not improved the outcome in terms of overall and progression-free survival in comparison to a low-intensity therapy. Yet, high-intensity bridging therapy was associated with more adverse events. Our study suggests that a low-intensity bridging regimen may be preferred whenever tumor burden and disease kinetics allow this treatment strategy.

1. To the editor,

We present clinical data on the treatment of relapsed/refractory (r/r) B-lineage acute lymphoblastic leukemia (B-ALL) prior to chimeric antigen receptor (CAR) T cells. CARs targeting CD19 have become a well-established therapeutic option for patients with r/rALL [1, 2]. In the period between eligibility for commercially available CAR T cells and their infusion an adequate “bridging therapy” (BT) is necessary to protect patients from rapid disease progression and to lower a pre-existing leukemia burden considering that a high tumor burden prior to infusion has been shown to be associated with worse overall survival (OS) and more post-CAR toxicity [1, 3,4,5,6,7]. This retrospective study is a collaboration of pediatric and adult hemato-oncology centers in Germany, Austria and Switzerland focusing on the differentiation of chemotherapeutic regimens regarding their intensity as well as immunotherapy and targeted therapy. We strive to improve the basis for clinical decision making in BT prior to CAR T cells.

Findings

88 patients (93 treatments) met inclusion and exclusion criteria (Fig. 1A-B). Details of the patient characteristics are shown in Table 1 (1 treatment could not be classified). Distribution of bridging regimens over the total bridging phase is shown in Fig. 1C. Median OS of all patients was 2.85 years (n = 85), median progression-free survival (PFS) 1.49 years (n = 81). Patients in the low-intensity and high-intensity groups had significantly shorter OS than patients in the no systemic therapy group (p = 0.0297 and p = 0.0307) (Fig. 1F). There was no significant difference in PFS between the groups (Fig. 1G). Patients who subsequently received no systemic therapy had a significantly lower bone marrow (BM) disease burden (M1 vs. M2-M3) at eligibility than patients who received a low- or high-intensity therapy (p = 0.0180; p = 0.0002). At lymphodepletion, there was no longer a significant difference (Fig. 1D). Also, minimal residual disease (MRD) was significantly higher in the high-intensity group at all time points (adjusted p = 0.0122) (Fig. 1E). Performance status of all patients did not differ significantly between beginning and end of BT (p = 0.0696) nor between the therapy groups at both time points (adjusted p = 0.2075; adjusted p = 0.1173) (Suppl. Figure 4C-D). Patients in the no therapy/low-intensity group had significantly higher numbers of extramedullary manifestations in comparison to the patients in the high-intensity group at eligibility and leukapheresis (p = 0.0015; p = 0.0223) (Suppl. Figure 4E). The most frequent adverse events (AE) were hematological AEs (Fig. 1H, Suppl. Table 2). Significantly more patients in the high-intensity group suffered from other toxicities (p = 0.0190) and the subgroup mucositis (p = 0.0108) (Fig. 1I). Bacterial AEs occurred significantly more frequently in the high-intensity group in comparison to the no therapy/low-intensity group (p = 0.0052) (Fig. 1I) and the severity level CTCAE 3–5 was significantly more frequent (p = 0.0015) (Suppl. Figure 6C). Viral and fungal AEs occurred equally frequently in the groups (p = 0.7702; p = 0.6943) (Fig. 1I). Extended results can be found in the supplementary material.

Fig. 1

A Stratification of bridging regimens. 1/93 treatments could not be stratified to one of the bridging regimens due to incomplete data. In case of incomplete data, patients were stratified to the high-intensity group if the administration of at least one high-intensity drug was definite. Hence, the above given numbers in the high-intensity subgroups are minimal values. CP cyclophosphamide, Ifo ifosfamide, iv intravenous. B Flow chart of inclusion and exclusion of patients according to study criteria. LBL lymphoblastic lymphoma. C Relative number of therapy regimens over the entire bridging phase. D Status of blasts in BM dichotomized in M1 and M2—M3, shown for the three groups “no therapy", “low-intensity” and “high-intensity”. The no therapy group had a highly significant lower BM-status at eligibility than patients who received a low- or high-intensity therapy (p = 0.0180 and p = 0.0002). There was no significant difference in BM-status between patients who subsequently received a low- or high-intensity treatment at eligibility (p = 0.0780). At lymphodepletion, there was no longer a significant difference between therapy groups. Blast count data were not available for all patients. Data were available for the following number of patients at eligibility: “no therapy” n = 13; “low-intensity” n = 35; “high-intensity” n = 30. Data were available for the following number of patients at lymphodepletion: “no therapy” n = 9; “low-intensity” n = 31; “high-intensity” n = 31. E Minimal residual disease (MRD) in bone marrow, shown according to intensity stratification at eligibility, leukapheresis and lymphodepletion. Whiskers graph the 10th to 90.^th percentile. At all time points, patients in the high-intensity group had a significantly higher MRD in comparison to patients in the no therapy/low-intensity group (adjusted p = 0.0122 for all time points). MRD data were not available for all patients. Data were available for the following number of patients at eligibility: “no therapy/low-intensity” n = 36; “high-intensity” n = 23. Data were available for the following number of patients at leukapheresis: “no therapy/low-intensity” n = 19; “high-intensity” n = 17. Data were available for the following number of patients at lymphodepletion: “no therapy/low-intensity” n = 24; “high-intensity” n = 24. F OS graphed according to intensity stratification. Patients in the no therapy group had a significantly better OS in comparison to the low- and high-intensity groups (p = 0.0297 and p = 0.0307). OS of low- and high-intensity groups did not differ significantly (p = 0.8579). G PFS graphed according to intensity stratification. PFS did not differ significantly between groups (no therapy vs. low-intensity p = 0.3723; no therapy vs. high-intensity p = 0.1530; low-intensity vs. high-intensity p = 0.4758). H Absolute number of adverse events (AEs) over the entire bridging phase. I) Percentage of patients with hematological AEs comparing no therapy/low-intensity group vs. high-intensity group (no significant difference, p = 0.2593). Percentage of patients with other toxicities comparing no therapy/low-intensity group vs. high-intensity group with significantly more other toxicities in the high-intensity group (p = 0.0190). Percentage of patients with bacterial AEs comparing no therapy/low-intensity group vs. high-intensity group with significantly more bacterial AEs in the high-intensity group (p = 0.0052). Percentage of patients with viral AEs comparing no therapy/low-intensity group vs. high-intensity group (no significant difference, p = 0.7702). Percentage of patients with fungal AEs comparing no therapy/low-intensity group vs. high-intensity group (no significant difference, p = 0.6943). Percentage of patients with mucositis comparing no therapy/low-intensity group vs. high-intensity group with significantly more mucositis in the high-intensity group (p = 0.0108). Percentage of patients with fever in neutropenia comparing no therapy/low-intensity group vs. high-intensity group (no significant difference, p = 0.3830)

Table 1 Patient characteristics

Discussion

Considering the increasing importance of CAR T cell therapy for r/r ALL patients, additional clinical data for BT are urgently needed to substantiate treatment recommendations. Built on knowledge of toxicity potential and clinical experience, we decided to utilize a pragmatic stratification strategy allocating patients into a “no systemic therapy” group, a “low-intensity” and a “high-intensity” group. A distinction according to the administered drug amount might appear reasonable, but there are no data suggesting a clear cut-off in drug doses of these agents. Currently, there is no evidence available that difference in percentage of BM blasts at time of eligibility to CAR T cell therapy is relevant for the prognosis. A prospective study is necessary to investigate if patients with a relatively higher tumor burden at time of eligibility can reach the low tumor burden being treated with a low-intensity chemotherapy regimen, considering that treatment decisions are expected to include individual considerations together with generalized therapy recommendation. In conclusion, in our retrospective study a low-intensity bridging approach had significantly less side effects and no disadvantage in outcome of PFS and OS. Together with a recently published guidance on BT [8], this and other retrospective data [9] support the collection of prospective data, validating low-intensity bridging approaches for the majority of r/r-ALL patients and identify those that require different treatment regimens.

Competing Interests

The authors declare no competing interests.