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Table 1 Major clinical trials on monoclonal antibodies treating acute lymphoblastic leukemia

From: Novel immunotherapies for adult patients with B-lineage acute lymphoblastic leukemia

Targets Medications Patients Regimens Outcome Study
CD20 Rituximab 216 pts with de novo Ph-negative B ALL; median age was 46 years (range, 16–84) Combination of hyper-CVAD plus rituximab CRD and OS were better with the combination of hyper-CVAD plus rituximab than with hyper-CVAD alone (69 vs 38%; P < .001 and 71 vs 47%, P = .003) for the younger pts (age < 60 years) Phase III [8]
220 pts aged 18–59 years old with newly diagnosed CD20-positive Ph-negative B cell precursor (BCP) ALL Rituximab (375 mg/m2) was added to pediatric-inspired GRAALL protocol from induction to the first year of maintenance for a total of 16 to 18 infusions After induction ± salvage reinduction, CR rate was 92 and 91% in the rituximab and control arm. Pts treated in the rituximab arm had a lower CIR (2-year CIR, 18 vs 30.5% in the control arm; p = 0.02) and longer EFS (2-year EFS, 65 vs 52% in the control arm; p = 0.038), but not longer OS (2-year OS, 71 vs 64% in the control arm; p = 0.095) Phase III [9]
Ofatumumab 55 pts with de novo ALL and 4 pts in CR previously treated; median age was 41 years (18–71) Hyper-CVAD in combination with ofatumumab
Ofatumumab given on courses 1 and 3, and 4 courses of MTX-Ara-C
98% CR rate after cycle 1, 53 (93%) pts achieved MRD negativity.
The 3-year CRD and OS rates were 78 and 68%, respectively
Phase II [13]
CD19 Blinatumomab 116 pts with Ph-negative BCP ALL with hematologic CR and MRD ≥ 10− 3 after ≥ 3 intensive chemotherapy treatments;
Median age was 45 years (18–76)
4-week continuous IV infusion, followed by a 2-week break (1 cycle). MRD responders in cycle 1 received up to 3 additional cycles or underwent HSCT Complete MRD response after the first cycle was 78%; complete MRD response rate was 80%. Median OS and RFS were 18.9 and 36.5 months, respectively Phase II [26]
36 pts with R/R pre-B ALL; median age was 32 years (18–77) 4-week continuous infusion followed by a 2-week interval 69% hematologic response and 88% of the responders also obtaining a molecular response (MRD level below 10− 4 by PCR) within the first 2 cycles Phase II [27]
CD22 Epratuzumab 30 pts with R/R CD22+ B ALL; median age was 35 years (21–59) 360 mg/m2/day on days 1, 8, 15, and 22, combined with hyper-CVAD The ORR was 50% including 9 CR (30%), 1 CRi (3%), and 5 PR (17%). All pts have died (during aplasia n = 3, progression n = 23, multiple organ failure n = 1), except the 3 responders still in CR, but yet recently enrolled Phase II [37]
31 pts with R/R Ph-negative B ALL. Median age was 41 years (21–69) Clofarabine 40 mg/m2/day on days 2–6, cytarabine 1 g/m2/day on days 1–5, epratuzumab 360 mg/m2/day on days 7, 14, 21, and 28 10 pts achieved CR and 6 achieved CRi for a CR/CRi rate of 52%. The median OS was 5 months Phase II [38]
Inotuzumab ozogamicin 90 pts with R/R pre-B ALL; median age was 39.5 years (range 4–84) INO single-dose at 1.8 mg/m2 every 3–4 weeks, n = 49; INO weekly at 0.8 mg/m2 on day 1 and at 0.5 mg/m2 on days 8 and 15, every 3 to 4 weeks, n = 41 17 pts (19%) CR, 27 (30%) CRp, and 8 (9%) marrow CR (no recovery of counts). ORR was 58%. Response rates were similar single dose and weekly dose (57 vs 59%). The median survival was 6.2 months: 5.0 months with single dose and 7.3 months with weekly dose Phase II [40]
326 CD22-positive, R/R ALL pts underwent randomization, the first 218 (109 in each group) were included in the analysis of complete remission INO group: INO (0.8–0.5 mg/m2, weekly, 3 times per cycle; cycle length, 21–28 days; total number of cycles, 6); standard intensive chemotherapy: FLAG for up to 4 cycles, cytarabine plus mitoxantrone for up to 4 cycles, or high-dose cytarabine for up to 1 cycle CR rate was higher with INO than with standard therapy (80.7 vs. 29.4% p < 0.001) and a higher percentage of pts in the INO group achieved < 0.01% MRD (78.4 vs. 28.1%, P < 0.001). Both PFS and OS were longer with INO (median PFS, 5.0 vs. 1.8 months, P < 0.001; median OS, 7.7 vs. 6.7 months, P = 0.04) Phase III [41]
57 pts with R/R CD22+ B ALL received mini-hyper-CVD regimen Mini-hyper-CVD regimen plus INO administered on day 3 of each of the first 4 cycles, rituximab (in pts whose cells were CD20-positive) and intrathecal chemotherapy were given for the first 4 courses The ORR was 71%: 31 (53%) CR, 13 (23%) CRp, and 1 (2%) CRi.
27 (47%) pts proceeded to receive allo-HSCT. Pts who were treated with mini-hyper-CVD plus INO had a higher PFS rate and improved OS compared to a historical cohort with single-agent INO in R/R ALL (2-year PFS; 52 vs 36%; p = 0.20: 2-year OS; 44 vs. 25%; p = 0.01)
Phase II [42]
   46 pts ≥ 60 years with newly diagnosed B cell ALL. Median age is 68 years (60–81) Mini-hyper-CVD regimen plus INO given on day 3 of each of the first 4 cycles. Rituximab (in pts whose cells were CD20-positive) and intrathecal chemotherapy were given for the first 4 courses Of the 42 pts evaluable for response, 40 (95%) achieved CR/CRp (35 CR, 5 CRp). Of the 44 pts assessed for MRD, 41 (93%) achieved negative MRD (71% of them at CR). The mini-hyper-CVD + InO +/− rituximab (n = 46) results appear superior to the historical data with HCVAD +/− rituximab (n = 46) (3-year OS of 52 and 36%, respectively, p = 0.05). Phase II [43]
CD52 Alemtuzumab 24 pts with de novo ALL in CR1. Median age was 37 years (18–77) A target dose of 30 mg administered 3 times per week for 4 weeks (12 doses) during post-remission therapy Of 11 pts assessed for MRD, 8 had a 1-log reduction. After 51 months of follow-up, median OS was 55 months and DFS was 53 months Phase I [44]
12 pts with relapsed (n = 11) or refractory (n = 1) ALL, including four relapses post-HSCT Alemtuzumab combined with granulocyte-colony stimulating factor (G-CSF) 4 of 12 pts achieved CR, but all pts progressed within a few months and all but one died Phase II [45]
  1. Pts patients, CIR cumulative incidence of relapse, OS overall survival, CRD complete remission duration, CR complete remission, MRD minimal residual disease, RFS relapse-free survival, DFS disease-free survival, R/R refractory/relapsed, CRp complete remission in the absence of total platelet recovery, CRi complete remission with incomplete hematologic recovery, ORR overall response rate