Background
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] |
Targets | Medications | Side effects |
---|---|---|
CD20 | Rituximab | Most common side effect is mild to moderate infusion reactions. Rare cases of severe mucocutaneous reactions, HBV reactivation, and progressive multifocal leukoencephalopathy |
Ofatumumab | Primarily grade 1 or 2 infusion reactions or infections | |
CD19 | SAR3419 | Dose-limiting reversible severe vision changes associated with corneal changes |
SGN-CD19A | Superficial microcystic keratopathy | |
Blinatumomab | Fever, chills, and hypogammaglobulinemia are common. Serious side effects include CRS and neurotoxicity | |
CD22 | Epratuzumab | Seizure, liver toxicity |
INO | Liver toxicity, veno-occlusive disease in transplant patients | |
CD52 | Alemtuzumab | Severe neutropenia, CMV viremia |
CD20-targeting agents—rituximab, ofatumumab, and GA101
Rituximab
Ofatumumab
Obinutuzumab (GA101)
CD19-targeting agents—SAR3419, SGN19a, and blinatumomab
SAR3419
SGN-CD19A
Blinatumomab
CD22-targeting agents—epratuzumab and inotuzumab ozogamicin
Epratuzumab
Inotuzumab ozogamicin (INO)
CD52-targeting agent—alemtuzumab
Chimeric antigen receptor T cell therapy
Clinical outcome of CD19-targeted CAR T cells in R/R ALL
Institution and trial no. | Costimulatory domain and gene transfer | Patient | Lymphodepleting chemotherapy | Cell dose | Outcomes |
---|---|---|---|---|---|
MSKCC NCT01044069 [53] | CD28, γ-retrovirus | Adults with R/R ALL including Ph + ALL, n = 44 | Cy or flu/cy | 1–3 × 106 cells/kg | CR: 36/43 (84%) with 29/35 (83%) of responders negative for MRD; OS: 76% (MRD-CR cohort) and 14% (MRD + CR cohort) at 6 months |
NCI NCT01593696 [54] | CD28, γ-retrovirus | Children and young adults with R/R ALL, n = 51 | Cy, low-dose flu/cy, FLAG, ifosfamide/etoposide or high-dose flu/cy | 0.03 × 106–3 × 106 cells/kg | CR: 31/51 (60.8%) with 28/31 (90%) of responders negative for MRD OS: 34.7% (receiving flu/cy) at 38 months LFS: 49.5% (MRD- CR) at 18 months LFS: 62% (MRD- CR cohort having a subsequent HSCT) at 18 months |
Multicenter studies NCT02614066, NCT02625480 [55] | CD28, γ-retrovirus | R/R ALL aged ≥ 18 years (ZUMA-3) or 2–21 years (ZUMA-4) with ≥ 25% marrow blasts Ph+ ALL and low-burden central nervous system disease are eligible | Flu/cy | 1 or 2 × 106 anti-CD19 CAR T cells/kg | CR: 5/5 (100%) |
FHCRC NCT01865617 [72] | 4-1BB, Lentivirus
| Adult with R/R ALL, n = 30 29 evaluable | Cy ± etoposide or cy/flu | 2 × 105 or 2 × 106 or 2 × 107 cells/kg 1:1 CD4+:CD8+ | CR: 27/29 (93%) |
UPenn/CHOP NCT01626495 [56] | 4-1BB, Lentivirus
| Children and young adults with R/R ALL, n = 53 | Investigator’s choice | 1–17.4 × 106 cells/kg | CR: 50/53 (94%) with 47/50 (94%) of responders negative for MRD OS: 78% at 12 months RFS: 72% at 6 months |
ELIANA (global trial) NCT02435849 [57] | 4-1BB, Lentivirus
| Children and young adults with R/R ALL, 29 pts reaching D28 prior to the data cutoff | Flu/cy | 0.2–4 × 106 cells/kg | CR: 24/29 (83%) with all of responders negative for MRD |
ENSIGN (US multicenter trial) NCT02228096 [58] | 4-1BB, Lentivirus
| Children and young adults with R/R ALL, n = 29 | Flu/cy, or none due to leukopenia | 2–5 × 106 cells/kg for ≤ 50 kg, 1–2.5 × 108 cells for > 50 kg | ORR (CR + CRi): 20/29 (69.0%) with 18/29 (62.1%) responders negative for MRD RFS: 66.4% at 6 months OS: 75.7% at 6 months |
UPenn/CHOP NCT02374333 [74] | 4-1BB, Lentivirus humanized anti-CD19 scFv domains | Children and young adults with R/R ALL, with or without prior exposure to a CAR T cell product, n = 30 | Flu/cy | No mention | CR: 26/30 (87%) CR for patients previously treated with CAR T: 7/11(64%) with 5/7 (71%) of responders negative for MRD CR for patients with no prior exposure to CAR T: 19/19 (100%) with 19/19 (100%) of responders negative for MRD |