Blinatumomab
The human CD19 antigen is a transmembrane protein expressed from pre-B cells until the terminal differentiation to plasma cells [
42]. CD19 is a critical component of B cell receptor multicomplex [
43]. Therefore, CD19 remains as the most reliable surface biomarker for B cells [
44,
45]. CD19 is the most commonly targeted antigen to date in immunotherapy for hematological malignancies [
46‐
48].
Blinatumomab (blina) is a novel first-in-human BiTE antibody against CD19/CD3 that is designed to bind specifically to CD19+ B cells and CD3+ T cells, resulting in T cell activation and a cytotoxic T cell response against CD19-expressing cells [
49]. Blina is produced through recombinant DNA technology [
50‐
54]. Blina is an antibody fragment with a molecular weight of 55 kDa. Therefore, its biological half-life is short and continuous IV infusion is required [
55,
56]. Similar to the infusion of CAR T cells, cytokine release syndrome (CRS) and neurotoxicity are the major adverse events from blina therapy [
25,
57‐
60]. In order to minimize CRS and neurotoxicities, it is recommended that the drug be used in a dose-escalating manner, with 9 μg/day for the first week, followed by 28 μg/day for the remaining 3 weeks [
25,
51,
59]. Two weeks of treatment-free interval are recommended prior to the subsequent cycle. The FDA approved indications, dose, and schedules of blinatumomab administration are summarized in Table
1.
Table 1
Blinatumomab for B cell precursor acute lymphoblastic leukemia
CR1 or CR2 with *MRD-positive patients |
Cycles 1–4 |
Days 1–28 | 28 μg/day | 15 μg/m2/day (not to exceed 28 μg/day) |
Days 29–42 | 14-day treatment-free interval | 14-day treatment-free interval |
Relapsed or refractory patients |
Induction cycle 1 |
Days 1–7 | 9 μg/day | 5 μg/m2/day (not to exceed 9 μg/day) |
Days 8–28 | 28 μg/day | 15 μg/m2/day (not to exceed 28 μg/day) |
Days 29–42 | 14-day treatment-free interval | 14-day treatment-free interval |
Induction cycle 2 |
Days 1–28 | 28 μg/day | 15 μg/m2/day (not to exceed 28 μg/day) |
Days 29–42 | 14-day treatment-free interval | 14-day treatment-free interval |
Consolidation cycles 3–5 |
Days 1–28 | 28 μg/day | 15 μg/m2/day (not to exceed 28 μg/day) |
Days 29–42 | 14-day treatment-free interval | 14-day treatment-free interval |
Continued therapy cycles 6–9 |
Days 1–28 | 28 μg/day | 15 μg/m2/day (not to exceed 28 μg/day) |
Days 29–84 | 56-day treatment-free interval | 56-day treatment-free interval |
A phase II multicenter clinical trial evaluating the safety and efficacy of blinatumomab in adult R/R Ph− B-ALL reported 43% CR rate [
59]. Among these CR patients, 24–46% were then able to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) [
25,
59,
61]. Blinatumomab is thus considered as an effective bridge therapy to allo-HSCT. The US FDA approved blinatumomab for the treatment of adult R/R Ph− B-ALL based on the phase II study [
59]. Subsequently, a large randomized phase III trial comparing blinatumomab versus salvage chemotherapy for R/R B-ALL was reported [
25]. This study enrolled 405 patients and randomized patients in a 2:1 ratio to receive blinatumomab (271 patients) or chemotherapy (134 patients). Compared to the chemotherapy group, the blinatumomab group had a significantly longer overall survival (OS) (7.7 months vs 4.0 months, HR 0.71,
p = 0.01) and a higher complete remission (CR) rate (44% vs 25%,
p < 0.001), further supporting blinatumomab as an efficacious and well-tolerated single-agent treatment option for R/R ALL.
Blina was also studied in B-ALL patients who had MRD+ after 3 months’ frontline therapy or those who relapsed with MRD disease [
61]. These patients were treated with blina following standard protocols up to 4 additional cycles. Patients who did not receive allo-HSCT were given maintenance blina therapy every 3 months for 4 cycles (a total of 9 cycles). TKI was added for Ph+ ALL patients at the discretion of treating physicians. A total of 17 patients were enrolled, with 3 Ph+ patients. Thirteen out of 17 patients (76%) achieved MRD negativity, with 12 of the 13 patients being MRD negative after the first cycle. Six of the 13 (46%) patients received allo-HSCT due to donor availability. In a separate multicenter open-label single-arm study from Europe, blina treatment was given to adult B cell ALL patients with +MRD in CR1 or CR 2/3 which was defined by flow cytometry or PCR [
62]. Among the 113 evaluable patients treated with blina, 88 patients (78%) achieved MRD negativity. The median OS was 36.5 months. When the patients with complete MRD negativity (MRD responders) were compared with those in persistent +MRD (non-responders), MRD responders had longer relapse-free survival (RFS) (23.6 vs 5.7 months;
p = .002) and OS (38.9 vs 12.5 months;
p = .002) than those in MRD non-responders. Therefore, it appears that blina is a good option to eliminate MRD after initial induction chemotherapy [
63].
Blinatumomab has been approved for Ph− B cell R/R ALL. To evaluate the activity of blina in Ph+ R/R ALL patients, a phase II trial was started. The primary end point of the study was CR/CRh. In the first report of 45 such patients, CR/CRh was shown to be 36% (95% CI, 22% to 51%) during the first 2 cycles [
64]. The responders included four of ten patients with the T315I mutation. Furthermore, the quality of the responses was striking, with MRD negativity in 88% of CR/CRh responders. Seven of the 16 responders (44%) proceeded to allo-HSCT. The secondary endpoints of the study included median RFS and OS, which were 6.7 and 7.1 months, respectively. The major adverse events were similar to those reported in Ph− R/R ALL patients. The CRS and neurotoxicities were mild without grade 4 or 5 neurologic events.
Nevertheless, the 43% CR rate from blina in R/R ALL means that a significant proportion of patients was still considered treatment-resistant. The mechanisms of resistance to blinatumomab therapy are still poorly understood. One case report described that blinatumomab treatment failure was associated with an increase in number of ALL cells positive for programmed death-ligand 1 (PD-L1), which may be one of the underlying immune escape mechanisms [
65]. This indicates that further investigation on the therapeutic potential of inhibitors of immune checkpoint molecules needs to be considered to overcome blinatumomab resistance. Another mechanism may be due to CD19 antigen loss as this was reported in relapsed patients after blina therapy [
66,
67], though this appears to be less common than those seen after CAR T therapy [
28,
68,
69]. To overcome this problem, a number of ongoing studies are evaluating combination of blinatumomab with chemotherapy for Ph− ALL and with TKI for Ph+ ALL.
A recent update reported the outcome of blina treatment in pediatric patients with R/R B ALL in an expanded access study [
70]. Treatment-emergent (TE) and treatment-related (TR) adverse events (AEs) were the primary endpoints. Morphologic CR and MRD response by PCR or flow cytometry were the secondary endpoints. At the time of the report, 98 patients were treated (median age, 8.5 [range 0.4–17.0] years). The median follow-up was 12.2 months (range 0.5–14.1). These patients were heavily pretreated. A median of 2 cycles (range 1–5) were administered, with 4 patients completing 5 cycles of blina. Virtually all patients experienced a TEAE whereas 77% had TRAEs. CRS was seen in 16%, with 2% severe. There were 9 grade 5 fatal AEs unrelated to blina treatment. Among the 98 patients, 60% (
n = 59) achieved CR and 48% had MRD negativity. Among the 59 CR patients, 27 (46%) proceeded to allo-HSCT. The median OS was 13.0 months. In conclusion, blina induced MRD negativity in almost half of the patients, including patients with t(17;19). In this study, 4 patients who had prior blina treatment were re-treated and 3 achieved CR again. Blina has now been approved as a treatment option for pediatric patients with R/R ALL (Table
1).
Another retrospective analysis reported data on blina for CNS disease in 11 patients with B ALL [
71]. Among the 11 patients, 10 had R/R ALL, 6 had Ph− ALL and 3 with Ph+ ALL. Of the 11 patients, 10 had systemic disease, only 1 with CNS only disease. Among the 11 patients who received blina, 3 had single agent blina, 4 in combination with BCR-ABL TKI, and 4 in combination with systemic chemotherapy. Intrathecal chemotherapy was given to all patients. Severe CNS toxicity was reported in 2 patients. Five of the 6 patients (83%) with active CNS disease became negative in CSF after blina therapy. There were 3 patients with positive CNS leukemic involvement on imaging studies. Among these 3 patients, 1 had CR, 1 had PR, and 1 had signs of inflammation. In conclusion, blina is safe and effective in B ALL patients with active CNS disease when given in combination with systemic and intrathecal chemotherapy. Currently, it remains unclear whether blina can penetrate the blood-brain barrier. In this regard, CAR T cells appear to have an advantage for CNS disease since it has been reported that CAR T cells were found in the CSF and are effective against CNS diseases in both hematological and solid tumors [
72‐
75].
CRS is one of the major complications from blina therapy [
50,
59]. IL-6 cytokine is found to be elevated and believed to be a major mediator of CRS [
74,
76]. In a recent analysis updated at the 2018 ASH Annual Meeting, CRS was reported in 39 cases out of 1000 patients treated with blina [
77]. Six of the 39 cases received tocilizumab, an IL-6 receptor antibody, 3 of the 6 patients received concurrent corticosteroids. Blina was interrupted and later restarted once CRS is resolved. CRS in all 6 cases resolved, and 3 cases resumed blina infusion. Among the 6 cases, 4 cases discontinued blina therapy. Recent studies on CAR T related toxicities have indicated that IL-1 and IL-6 are mediators of CRS, and IL-6 antagonist does not abrogate cytotoxicity of CAR T cells [
57,
78,
79]. It is therefore possible that tocilizumab and IL-1 receptor antagonist may be used early as prophylaxis in addition to therapy. Clinical studies are ongoing for these clinical applications [
57].