Real-world efficacy of CAR T cells for posttransplant relapse in patients with B-ALL

Patients with acute lymphoblastic leukemia (ALL) who do not respond to chemotherapy and relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have a poor prognosis. Novel cellular immunotherapies, such as CD19-directed chimeric antigen receptor (CAR) T cells, are being investigated for this high-risk patient population. The efficacy of CAR T-cell therapy has been confirmed in large studies of patients with precursor relapsed and refractory (R/R) B-cell ALL (B-ALL).

Here, we summarize a real-world retrospective study involving CAR T-cell centers in Germany that were approved to perform treatment with tisagenlecleucel (tisa-cel). The centers were asked to collect treatment data reflecting post-approval reality to verify clinical trial outcome data. In addition, the study aimed to identify patients who would benefit most from this tisa-cel treatment.¹

Study design

The study was conducted between September 1, 2018, and January 1, 2022. Included patients had B-ALL, received tisa-cel, were aged ≤25 years, and had primary refractory disease, ≥2 relapses, or had relapsed after allo-HSCT.

Results

Patient characteristics

A total of 81 patients were included and the baseline characteristics were similar between patients with/without prior allo-HSCT (Table 1).

Table 1. Patient characteristics*

HSCT, hematopoietic stem cell transplantation; LDC, lymphodepleting chemotherapy; NA, not applicable. *Adapted from Bader, et al.1
Characteristic, % (unless otherwise stated)	All patients (N = 81)	With HSCT (n = 65)	Without HSCT (n = 16)
Median age (range), years	11.5 (1–25)	10 (1–25)	14.5 (1.2–25)
Female	34.6	35.4	31.2
Male	65.4	64.6	68.8
Preliminary treatment
Primary                refractory	1.2	0.0	6.2
Relapsed                refractory	18.5	0.0	93.8
HSCT	80.2	100.0	NA
Cytogenetics
Favorable	13.6	10.8	25.0
Intermediate                risk	50.6	50.8	50.0
High risk	35.8	38.5	25.0
Remission status at LDC
<5% blasts	54.3	50.8	68.8
≥5% blasts	45.7	49.2	31.2

The results showed that patients with refractory or relapsed disease, including patients who relapsed after allo-HSCT, could be rescued with a single infusion of CAR T cells.

Safety

CRS and ICANS

• Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were less frequent in the real-world study versus the ELIANA trial.
  • CRS: 67.9% vs 77.3%, respectively
  • ICANS: 7.4% vs 40%, respectively
• The risk of CRS was not significantly different between those who had previously had HSCT compared to those who had not (64.6% vs. 81.2%; p = 0.20).

Non-relapse events

• Two patients developed fulminant, severe CRS (Grade V) and macrophage activation that could not be controlled; the patients died 1.2 months and 0.8 months post CAR T-cell infusion.
• Two patients died of treatment-related mortality due to infection or multiorgan toxicity at 4.6 or 1.2 months after CAR T-cell infusion.
• One patient with a prior allo-HSCT followed by CAR T-cell treatment developed secondary myelodysplastic syndrome.

Efficacy

Response

• Overall, 87.8% of patients achieved complete response; however, in 9.9% of patients, 28 days of CAR T-cell infusion failed to yield a response (Figure 1).

CAR, chimeric antigen receptor; CR, complete response; NR, no response.
*Adapted from Bader, et al.¹

Survival

• At 2 years, the probabilities of event-free survival (pEFS), relapse-free survival (pRFS), and overall survival (pOS) were 45.3%, 51.7%, and 53.2%, respectively.
• The pEFS was not different in patients without vs with prior allo-HSCT (55.0% vs 4 3.4%, respectively).
• The analysis of potential risk factors, such as age, cytogenetics, sites of leukemia involvement, or intensity of LDC, showed that only disease burden at LDC was associated with pEFS. Patients with high-level disease (≥5%) had a pEFS of 29.6%, compared with 55.4% in patients with low-level disease (<5% blasts; p = 0.049)

Patients with previous allo-HSCT

Of the 81 patients involved in this study, 65 had received a prior allo-HSCT for high-risk or relapsed disease, and subsequently relapsed before receiving CAR T-cell therapy. With a relatively a high proportion of patients having received allo-HSCT, this was a unique population in real-world evidence and was therefore analyzed in detail.

Patients who relapsed within 6 months of receiving an allo-HSCT had a median follow-up of 28.8 months; they also had a lower pEFS compared with those relapsing more than 6 months after allo-HSCT. Furthermore, pOS and pRFS were lower in patients who relapsed within 6 months of allo-HSCT compared with patients who relapsed more than 6 months following allo-HSCT. Treatment failure was mainly due to relapse, with the cumulative incidence of relapse being higher for patients who had relapsed within 6 months of allo-HSCT compared with those who had relapsed beyond 6 months (68.5% vs 37.1%; p = 0.026). A comparison between pEFS, pOS, PRFS, and cumulative incidence of relapse is shown in Figure 2.

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; CIR, cumulative incidences of relapse; pEFS, probability of event-free survival; pOS, probability of overall survival; pRFS, probability of relapse-free survival.
*Adapted from Bader, et al.¹

Conclusion

This real-world study demonstrated promising outcomes with tisa-cel in patients with R/R B-ALL. The results showed that patients who relapsed after allo-HSCT could be rescued with a single infusion of tisa-cel. Furthermore, patients who relapsed ≥6 months after HSCT had improved survival outcomes with a single tisa-cel infusion and no further consolidation. Prospective studies should be undertaken to further elucidate how to improve outcomes in patients who relapse during the first 6 months after allo-HSCT.