Blinatumomab as first salvage versus second or later salvage in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia

Introduction

Relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) has poor outcomes in patients with survival of less than 6 months. The development of novel targeted therapies such as bispecific T-cell engager (BiTE) and chimeric antigen receptor (CAR) T-cell therapy have significantly improved outcomes in R/R ALL. However, there remains a discrepancy in the survival rates among patients with R/R B-cell precursor receiving first, second, third, or later salvage.  

Topp M. S. and colleagues recently published a study in Cancer Medicine, assessing the efficacy and safety of blinatumomab as first versus second or later salvage in patients with R/R B-cell precursor ALL.¹ The findings from this study are summarized below.

Study design

The study was a comparative analysis using patient level pooled data of 532 patients from two phase II, and one phase III study.²⁻⁴ The patients were aged ≥18 years, and had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

• Primary endpoints were overall survival (OS) and relapse-free survival (RFS).

Eligible patients included in the study received blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval (first salvage, n = 165; and second or later salvage, n = 367)

Results

Baseline characteristics¹

Patients receiving blinatumomab as first salvage were older and had had slightly better ECOG performance status compared with those receiving second or later salvage (Table 1). More than 25% of patients in both groups had prior allogenic hematopoietic stem cell transplant (allo-HSCT).

Table 1. Baseline characteristics.*

ECOG, Eastern Cooperative Oncology Group; allo-HSCT, allogeneic hematopoietic stem cell transplant. *Data from Topp et al.1
Characteristic	First Salvage (n = 165)	Second or later salvage (n = 367)
Median (range) age, years	45 (19−80)	34 (18−77)
Sex, n (%)               Men               Women	98 (59) 67 (41)	225 (61) 142 (39)
ECOG performance status, n (%)               0               1               2               Unknown	77 (47) 72 (44) 16 (10) 0 (0)	111 (30) 191 (52) 63 (17) 2 (1)
Prior allo-HSCT, n (%)	41 (25)	141 (38)
Median (range) bone marrow blasts at screening, %	78 (1−100)	81 (2−100)
Bone marrow blasts, n (%)               ≤ 5%               > 5%−< 10%               10%−< 50%               ≥ 50%               Unknown	8 (5) 9 (6) 35 (21) 99 (60) 14 (9)	8 (2) 13 (4) 78 (21) 250 (68) 18 (5)

Efficacy

OS and RFS

• Median OS was half in patients receiving blinatumomab as second or later salvage (5.7 months) compared with first salvage (10.4 months) (Table 2).
• The subgroup analysis showed that median OS was shorter in patients without prior allo-HSCT. However, the overlapping confidence intervals suggest that there was no difference in OS based on prior allo-HSCT status for the first or later salvage subgroups.
• Median RFS was also higher in patients who received blinatumomab as first salvage (10.1 months) compared with second or later salvage (7.3 months).
• There was no statistically significant difference between RFS among patients who received blinatumomab as first salvage compared with those with second or later salvage (HR, 1.38; 95% CI, 0.98–1.93; p = 0.061).

Table 2. OS and RFS.*

allo-HSCT, allogeneic hematopoietic stem cell transplant; CI, confidence interval; HR, hazard ratio; OS, overall survival; RFS, relapse-free survival. *Data from Topp et al.1
Patient group	Median OS, months (95% CI)	HR; p value
First salvage	10.4 (8.3−14.3)	1.58; p < 0.001
Second or later salvage	5.7 (4.3−7.1)
First salvage + prior allo-HSCT	14.7 (8.3−25.3)
First salvage + no prior allo-HSCT	9.3 (7.7−13.5)
Second or later salvage + prior allo-HSCT	7.4 (4.2−9.0)
Second or later salvage + no prior allo-HSCT	4.9 (3.9−6.7)
Patient group	Median RFS, months (95% CI)	HR; p value
First salvage	10.1 (7.4−18.0)	1.38; p = 0.061
Second or later salvage	7.3 (5.7−9.6)

Response and transplant realization

• Complete remission (CR) or CR with partial hematologic recovery (CRh) was higher in patients who received blinatumomab as first salvage (54%) compared with those who received second or later salvage (41%) (OR 0.59; p = 0.005) (Table 3).
• 47% of patients who received blinatumomab as first salvage achieved CR compared with 28% in patients who received blinatumomab as second or later salvage. CRh was achieved in 7% vs 13% of patients, respectively.
• Higher minimal residual disease (MRD) response was seen in patients receiving blinatumomab as first salvage. There was no difference in the rate of MRD response in patients with CR/CRh among both groups.
• There was also no difference in median OS among patients who received first salvage (15.9 months; 95% CI, 8.7−not estimable [NE]) or second and later salvage (20.8 months; 95% CI, 8.3−NE) who went on to receive allo-HSCT.

Table 3. Best response, MRD, and transplant.*

allo-HSCT, allogenic hematopoietic stem cell transplant; CI, confidence interval; CR, complete remission with full hematologic recovery; CRh, CR with partial hematologic recovery; Cri, CR with incomplete hematologic recovery; MRD, minimal residual disease. *Data from Topp et al.1 †Bone marrow blasts <10−4.
Best response, MRD, and transplant	First Salvage (n = 165), n (%) [95% CI]	Second or later salvage (n = 367), n (%) [95% CI]
Best response after two cycles CR or CRh CR CRh CRi	89 (54) [46−62] 78 (47) [40−55] 11 (7) [3−12] 1 (1) [0−3]	150 (41) [36−46] 101 (28) [23−32] 49 (13) [10−17] 3 (1) [<1−2]
MRD response after two cycles† MRD response MRD response among patients with CR/CRh	68 (41) [34−49] 63 (71) [60−80]	118 (32) [27−37] 106 (71) [63]
Patients with allo-HSCT	60 (36) [29−44]	88 (24) [20−29]
Patients transplanted in continuous remission post-blinatumomab	33 (20) [14−27]	52 (14) [11−18]
Patients with anti-leukemic treatment other than blinatumomab	42 (26) [19−33]	61 (17) [13−21]
Patients transplanted after relapse post-blinatumomab and/or refractory post-blinatumomab	4 (2) [1−6]	9 (3) [1−4]

Safety

• The incidence rates of treatment-emergent adverse events (AEs) and Grade ≥3 treatment-emergent AEs were similar across both groups (Table 4).
• The incidence rate of serious treatment emergent AEs was slightly lower among patients who received blinatumomab as first salvage compared with the second or later salvage (60% vs 66%).
• The percentage of patients with fatal treatment-emergent AEs was lower among those with first salvage compared with second or later salvage (10% vs 21%); however, the percentage was similar for treatment-related fatal AEs (2% vs 3%).

Table 4. Adverse events.*

AE, adverse event; CRS, cytokine release syndrome; TEAE, treatment-emergent AE. *Data from Topp et al.1
Event	First Salvage (n = 165)		Second or later salvage (n = 367)
	Any grade, n (%)	Grade ≥3, n (%)	Any grade, n (%)	Grade ≥3, n (%)
Patients with any TEAE	162 (99)	133 (81)	361 (99)	310 (85)
Patients with any treatment emergent serious AE	99 (60)	—	239 (66)	—
Patients with a fatal TEAE	16 (10)	—	76 (21)	—
Patients with a fatal treatment-related AE	3 (2)	—	10 (3)	—

Conclusion

The longer median OS and RFS are indicative of the greater benefit of blinatumomab as first salvage compared with second or later salvage. The safety profiles were similar across both groups except the incidence rate of serious treatment-emergent AEs, which was slightly higher among patients treated with second or later salvage. However, these findings should be considered in the context of some of the limitations of the study such as both groups were not well balanced in number and the impact of anti-CD22 monoclonal antibody was not evaluated.