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

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]