4,661
Views
3
CrossRef citations to date
0
Altmetric
Research Article

Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia

, , &

ABSTRACT

Objectives

This review aims to see the progress of several clinically-used monoclonal antibodies in treating ALL patients and how they improved patients' outcomes.

Methods

We searched Web of Science, Elsevier and PubMed for relevant published studies, and summarized eligible evidence on the management of newly-diagnosed and relapsed or refractory ALL with monoclonal antibodies. Ongoing trials were identified from ClinicalTrials.gov.

Results

Rituximab, an anti-CD20 monoclonal antibody, prolonged patients' complete remission duration and overall survival when combined with hyper-CVAD regimen. Another anti-CD20 monoclonal antibody, Ofatumumab, was reported to have similar benefits. Blinatumomab allows endogenous CD3-positive cytotoxic T cells to target and eliminate CD19-positive blasts. FDA has approved its efficacy in patients with R/R B-ALL and eliminating minimal residual disease (MRD). It serves as a bridge to eradicate MRD before transplantation, and may also be a new choice for patients unable to undergo transplantation. An anti-CD22 monoclonal antibody named Inotuzumab Ozogamicin showed great improvement in patients' outcome, but its toxicity to liver is also worthy of our attention.

Conclusion

Monoclonal antibodies are proven to be a promising immunotherapeutic strategy to improve ALL patients' outcome in the long term. There's still a need for individualized treatment with effective and well-tolerated medicines.

Trial registration: ClinicalTrials.gov identifier: NCT01363128.

Trial registration: ClinicalTrials.gov identifier: NCT01466179.

Trial registration: ClinicalTrials.gov identifier: NCT02013167.

Trial registration: ClinicalTrials.gov identifier: NCT02000427.

Trial registration: ClinicalTrials.gov identifier: NCT01564784.

Trial registration: ClinicalTrials.gov identifier: NCT03677596.

Trial registration: ClinicalTrials.gov identifier: NCT01363297.

Trial registration: ClinicalTrials.gov identifier: NCT02981628.

Trial registration: ClinicalTrials.gov identifier: NCT03094611.

Trial registration: ClinicalTrials.gov identifier: NCT01371630.

Trial registration: ClinicalTrials.gov identifier: NCT04224571.

Trial registration: ClinicalTrials.gov identifier: NCT02458014.

Trial registration: ClinicalTrials.gov identifier: NCT04546399.

Trial registration: ClinicalTrials.gov identifier: NCT02879695.

Trial registration: ClinicalTrials.gov identifier: NCT03913559.

Trial registration: ClinicalTrials.gov identifier: NCT03441061.

Trial registration: ClinicalTrials.gov identifier: NCT03739814.

Trial registration: ClinicalTrials.gov identifier: NCT02877303.

Trial registration: ClinicalTrials.gov identifier: NCT03698552.

Trial registration: ClinicalTrials.gov identifier: NCT04601584.

Trial registration: ClinicalTrials.gov identifier: NCT04684147.

Trial registration: ClinicalTrials.gov identifier: NCT04681105.

1. Introduction

Acute lymphoblastic leukemia (ALL) is a malignant hematological disease derived from the abnormal proliferation and accumulation of immature lymphocytes in the bone marrow, peripheral blood and extramedullary organs. It occurs most frequently in childhood, and reaches a second peak in patients over 60 years [Citation1]. Conventional treatment is based on multi-agent chemotherapy, typically consisting of an induction phase to reduce initial leukemic burden and obtain remission, a consolidation phase to eradicate residual blasts, a late intensification phase and long-term maintenance. Routine central nervous system (CNS) prophylaxis is recommended to start early, reducing the chance of relapse in CNS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recognized as a curative approach for suitable high-risk patients in certain subgroups.

Currently, the proportion of pediatric patients with long-term survival reaches up to nearly 90% [Citation2, Citation3]. While the majority of adult patients could achieve complete remission (CR) following upfront chemotherapy, their outcome in the long term is far from satisfying, owing to factors such as advanced age, poor tolerance to chemotherapy, higher rate of recurrence and higher-risk quality of the disease itself [Citation4–6]. Only about half of adult patients treated with conventional chemotherapy could survive for more than 5 years [Citation7]. The application of pediatric-inspired therapy and its further exploration of tolerable upper age limit has improved the rate of 5-year overall survival in first adolescents and young adults (AYAs), and then patients younger than 55 years old, to nearly 60%, and even to 80% in some cases [Citation8–11]. Meanwhile, the presence of minimal residual disease (MRD) also challenges the treating strategy with a higher rate of relapse.

Therefore, exploring effective and well-tolerated treatment strategies has been on going over the past decade. The development of monoclonal antibodies has been one of the most promising options due to their activity to enhance the efficacy of conventional chemotherapy without adding therapy-related toxicity by specifically targeting certain leukemia-associated antigens. Studies using monoclonal antibodies in the management of acute lymphoblastic leukemia are shown in . In this review, we focus on recent progress in how monoclonal antibodies being used in treating patients with ALL and improving their outcomes.

Table 1. Studies using monoclonal antibodies in the management of acute lymphoblastic leukemia.

1.1. Rituximab

CD20 is expressed during nearly all stages of differentiation on both normal and malignant B lymphocytes, but only 30-50% of precursor B-ALL blasts and increases the occurrence of relapse and death [Citation12–15]. Rituximab is a chimeric monoclonal antibody against CD20 and can trigger cytotoxic effects and induce apoptosis of leukemic cells. At present, adding Rituximab to upfront chemotherapy has shown considerable improvement in prognosis of patients with diffuse large-B-cell lymphoma, aggressive mantle-cell lymphoma, chronic lymphocytic leukemia (CLL) and Burkitt and Burkitt-type lymphoma/leukemia [Citation16–23].

In 2012, a pilot study reported 9 adult patients with CD20 + relapsed/refractory (R/R) B-ALL treated by the combination of Rituximab and chemotherapy, suggesting it may be a feasible approach to achieve CR and reduce MRD in this group of patients, but required larger series [Citation24]. The MD Anderson Cancer Center (MDACC) trial recruited 282 adolescents and adults with de novo Ph (Philadelphia chromosome) negative precursor B-cell lymphoblastic leukemia (BCP-ALL) and evaluated the efficacy of additional Rituximab into the standard treatment for patients with more than 20% CD20 expression. Based on the hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen, an effective first-line therapy in this subset, the incorporation of Rituximab demonstrated its superiority with better 3-year rates of CR duration (70%: 38%; P < 0.001) and 3-year overall survival (OS, time from treatment initiation to death or date of last follow-up) (75%: 47%; P = 0.003) in patients younger than 60 years old. But for the older patient group, prognosis was poorer regardless of the usage of Rituximab [Citation25].

In the meantime, the Group for Research on Adult Acute Lymphoblastic Leukemia 2005 (GRAALL-2005) trial enrolled 787 patients aged 18–59 with newly diagnosed Ph negative ALL between 2006 and 2014 from multiple centers in France and Switzerland. Among them, 220 patients with CD20 expression (assessed by a traditional 20% cut-off) were included in the GRAALL-2005/R study to test the potential benefits of Rituximab with chemotherapy prospectively. Eligible patients were randomized into two groups: 105 in the Rituximab group and 104 in the control group. For those in the Rituximab group, Rituximab was given throughout the course of induction, consolidation, and maintenance. After a median follow-up of 30 months, event-free survival (EFS) was longer (HR: 0.66; 95% confidence interval [CI]: 0.45–0.98; P = 0.04) and incidence of relapse was lower (HR: 0.52; 95%CI: 0.31–0.89; P = 0.02) compared with the control group. However, no significant difference was seen in OS between the two groups (HR: 0.70; 95%CI: 0.46–1.07; P = 0.10) [Citation26].

1.2. Ofatumumab

Ofatumumab, a human anti-CD20 monoclonal antibody, targets a distinct extracellular epitope from Rituximab. Due to its closer binding to the cell membrane, Ofatumumab was proved to promote a more potent complement-dependent cytotoxicity in vitro than Rituximab [Citation27, Citation28]. Ofatumumab has been demonstrated to be safe and effective in treating CLL and has gained approval by the US Food and Drug Administration (FDA) in 2014 [Citation29, Citation30]. Therefore, promising results may also exist in patients with ALL by introducing Ofatumumab to intensive chemotherapy.

Previous evidence suggests an increase in CD20 expression after induction. Relevant mechanisms are as follows. The instability of leukemic phenotypes makes it susceptible to external influences in cellular processes, and medical intervention especially glucocorticoid may trigger the up-regulation of CD20 expression during induction chemotherapy [Citation31, Citation32]. Based on these results, researchers hypothesized that patients whose CD20 expression level was less than 20% at diagnosis might also benefit from the treatment of anti-CD20 monoclonal antibodies.

The MD Anderson Cancer Center conducted a single-arm, phase 2 trial (NCT01363128) to recruit untreated Ph negative B-cell ALL patients with at least 1% of CD20 expression [Citation33]. All patients received hyper-CVAD therapy on course 1,3,5,7, and MTX-Ara-C therapy (high-dose methotrexate and cytarabine) on course 2,4,6,8. Ofatumumab was given for 2 separate days on course 1,2,3,4 with a total of 8 doses. During the following 30 courses of POMP therapy (6-mercaptopurine, vincristine, methotrexate, and prednisone) for maintenance, another 4 doses of Ofatumumab were given on course 6,7,18,19 as intensification on top of high-dose methotrexate and pegylated asparaginase. After a median follow-up of 44 months (26–53 months), two thirds of the patients were still alive, of which more than half (54%) remained in their first CR duration. For adolescents and young adults aging 18–39, 4-year EFS and OS were 69% and 74%, respectively, comparable to those treated with pediatric or pediatric-inspired regimens as previously reported [Citation34–40]. Of note, although patients with CD20 expression less than 20% were not eligible in previous studies focusing on Rituximab, this patient group could gain different levels of clinical benefits, and therefore, may also be indicated for the use of CD20 monoclonal antibodies. Infection was the most common grade 3 or 4 adverse event (AE), and none of the deaths were considered to be directly Ofatumumab-related.

2. Blinatumomab

CD19 is a B-lineage surface antigen essential for the development and survival of B cells, and is expressed on virtually all stages of B-lineage ALL. Its frequent expression on these blasts makes it an ideal target for the utilization of Blinatumomab, a bispecific T-cell engager (BiTE) antibody that enables endogenous CD3-positive cytotoxic T cells to recognize and eliminate CD19-positive B cells [Citation41, Citation42].

2.1. Study in Ph− R/R patients

In a phase 2 study (NCT01466179), 189 adult patients with Ph negative, R/R BCP-ALL were enrolled [Citation43]. Blinatumomab was administered based on a previous dose-evaluating study by continuous intravenous infusion in 6-week cycles. Patients received Blinatumomab for 4 weeks (9 μg/day for the first week in cycle one and 28 μg/day afterwards) and no treatment for 2 weeks [Citation44]. After the first two cycles of treatment, 33% patients achieved a CR (≤5% bone-marrow blasts, platelets >100,000/μL, and absolute neutrophil count >1000/μL) and 10% patients achieved a CRh (≤5% bone-marrow blasts, platelets >50,000/μL, and absolute neutrophil count >500/μL). Median relapse-free survival (RFS, time from remission to relapse, death, or censoring at last date of continuous remission) and median OS were 5.9 months (95%CI: 4.8–8.3) and 6.1 months (95%CI: 4.2–10.1), respectively. Among patients who had CR or CRh within 2 cycles and evaluated MRD status, 82% achieved MRD negativity. And MRD responders showed a significantly improved median RFS (6.9 months (95%CI: 5.5–10.1):2.3 months (95%CI: 1.2 – not estimable)) and median OS (11.5 months (95%CI: 8.5 – not estimable):6.7 months (95%CI: 2.0 – not estimable)) compared with MRD non-responders. Common grade 3 or 4 adverse events (AEs) included 25% febrile neutropenia, 16% neutropenia, and 14% anemia, and treatment-related deaths were few. This study advanced FDA approval of Blinatumomab in treatment of R/R Ph negative B-cell ALL.

In order to further verity the efficacy and safety of single-agent immunotherapy with Blinatumomab for adults with Ph negative R/R BCP-ALL, a multi-institutional phase 3 clinical trial (NCT02013167), also known as the TOWER trial, was conducted. Patients were assigned randomly to receive either Blinatumomab or standard chemotherapy in a 2:1 ratio. Obvious clinical benefits were reported in the Blinatumomab group with a significantly higher CR (34%: 16%; P < 0.001) within 12 weeks after treatment, as well as a 3.7 months’ extension of median OS (7.7 months: 4.0 months; HR: 0.71; P = 0.01), and a higher rate of 6-month EFS (31%:12%; HR: 0.55; 95%CI: 0.43–0.71; P < 0.001). AEs were common in both groups, and the Blinatumomab group had an overall lower rate of serious AEs and was also associated with a lower incidence of myelosuppression and related complications than the chemotherapy group [Citation45].

After 2 cycles of Blinatumomab induction, patients who achieved a bone marrow response (≤5% bone marrow blasts) or CR/CRh/CRi (platelets >100,000/μL, or absolute neutrophil count >1000/μL) could continue to use Blinatumomab for another 3 cycles of consolidation and long-term maintenance therapy. Thirty six of 271 patients finally entered maintenance therapy, of whom the median OS was not reached at the end of the study, and for those who discontinued Blinatumomab early, median OS was 15.5 months, with a relative odds ratio of 0.37 (95%CI: 0.16–0.88). The median RFS was 14.5 months (95%CI: 7.1–21.9) and 9.8 months (95%CI: 8.5–11.1) respectively for patients with or without maintenance therapy, with a relative odds ratio of 0.48 (95%CI: 0.22–1.03). The incidence of adverse events decreased from 97.2% during induction, to 86.1% during consolidation, to 72.2% during maintenance. Although the follow-up result was limited by its insufficient sample size, we could still consider Blinatumomab as a potential option for long-term treatment in R/R BCP-ALL [Citation46].

2.2. Study in MRD+ patients

MRD is the major cause of relapse, it can be detected by techniques such as flow cytometry and polymerase chain reaction (PCR). We normally define more than 10−4 detectable blasts as MRD positive. Treatment for patients with persistent or relapsed positive MRD is one of the trickiest issues in ALL therapy, considering the widely-accepted fact that MRD is always linked to a poor prognosis [Citation47–49]. In such condition, allo-HSCT was highly recommended, but the benefit was less satisfying due to the long waiting period of a suitable donor or a relatively higher chance of getting relapsed after transplantation [Citation50–53]. Early application of Blinatumomab maybe another feasible solution in this setting. In the phase 2 BLAST trial, Nicola et al. analyzed 116 B-ALL patients in hematological CR with MRD (≥10−3), the majority of which (78%) were able to obtain complete MRD response after receiving Blinatumomab. It was reported that complete MRD responders were associated with a significantly longer RFS (23.6 months: 5.7 months; P = 0.002) and OS (38.9 months: 12.5 months; P = 0.002) than MRD non-responders, and the treatment begun after first CR was more beneficial [Citation46]. The efficacy of Blinatumomab to eliminate MRD makes it the first FDA-approved therapy for patients with BCP-ALL in morphologic remission with minimal residual disease [Citation54].

In the final follow-up report of the BLAST trial, when every patient completed the 5-year assessment, median survival was reported to be not reached (29.5–NR) for those who had complete MRD response and 14.4 months (3.8–32.3) for those who were not (p = 0.002). Among those who underwent HSCT, median OS was NR and 16.5 months (p = 0.065) respectively for patients with or without MRD response, and for those who did not undergo HSCT, median OS was 56.4 and 6.2 months (p = 0.043) respectively [Citation55], suggesting that Blinatumomab may serve as an effective bridging therapy to eradicate MRD before HSCT, and for those who were not conditioned for HSCT, Blinatumomab could also be a promising option to achieve long-term survival. Similar result was reported in the subsequent study of the TOWER trial, where no significant benefit of HSCT was seen for patients who achieved complete remission with full, partial, or incomplete hematologic recovery with Blinatumomab (p = 0.69), but those with an MRD response in the first salvage therapy, regardless of their HSCT status had the best outcome. In addition, no unusual toxicities or increased risk and mortality were observed post-HSCT compared with the standard chemotherapy group [Citation56].

In a recent retrospective study, Blinatumomab also showed remarkable potential to reduce MRD in infant patients. After receiving 1 or 2 cycles of Blinatumomab, 2 of 11 (81.8%) patients achieved a complete MRD response prior to HSCT. Three-year EFS and OS were 47% and 81%, respectively, although limited by the small sample size, improvement was obvious compared with the historical cohort [Citation57–59], making it possible to reset the age limit for this therapy.

2.3. Study in Ph+ patients

The presence of Ph chromosome is one of the most common chromosomal abnormalities in ALL patients with an incidence of approximately 15–30%. It used to be associated with an inferior prognosis, however, since the introduction of tyrosine kinase inhibitors (TKIs), patients’ outcomes have been greatly improved with the 5-year OS increasing from 10% to 40%–50% [Citation60–65]. But for patients who get relapsed after the treatment of TKI-based therapy, or are refractory or intolerant to TKIs, options are limited to achieve a long-term survival.

A single-arm, multicenter, phase 2 study (NCT02000427) was conducted to explore the possibility and efficacy of single-agent Blinatumomab in this patient population. 45 patients were included, and Blinatumomab was administered in 28-day cycles. Anti-leukemia activity was revealed with a 36% of CR/CRh rate after the first two cycles, of which 88% also achieved a complete MRD response. Median RFS and OS were 6.7 and 7.1 months, respectively. Frequent AEs involved pyrexia (58%), febrile neutropenia (40%), and headache (31%), consistent with those observed in previous Ph negative ALL studies [Citation66]. In the subsequent propensity score analysis (PSA), an external cohort was established by patients with similar baseline characteristics and receiving standard of care (SOC) chemotherapy instead of Blinatumomab (n = 55) from the existing databases. The rate of CR/CRh was 36% in the Blinatumomab cohort versus 25% in the SOC cohort, leading to an odds ratio of 1.54 (95%CI: 0.61–3.89) or 1.70 (95% credible interval [CrI]: 0.94–2.94) with Bayesian data augmentation. The Bayesian-augmented (80% power) hazard ratio estimate for OS was 0.77 (95%CrI: 0.61–0.96), suggesting a 23% reduction in the risk of death in the Blinatumomab group compared with the SOC group [Citation67].

Couturier, MA et al retrospectively analyzed 26 patients with R/R Ph+ ALL, the conjunction of Blinatumomab and Ponatinib also showed promising results with 25 of 26 patients achieving complete morphologic remission, and 23 achieving a complete molecular response. The median OS and EFS were 20 and 15.3 months, respectively, with a median follow-up of 34.4 months. No significant difference of OS or EFS was found in patients proceeding to allo-HSCT or not [Citation68]. Another retrospective study examined 11 Ph+ ALL patients treated with concurrent Blinatumomab and TKIs. After a median treatment of one cycle, 8 of 9 patients in positive MRD status achieved complete molecular response (CMR), 2 remaining patients without detectable MRD maintained CMR, suggesting that the combination of Blinatumomab and TKIs may be used as a consolidation therapy to obtain MRD negativity and sustain CMR [Citation69].

3. Inotuzumab Ozogamicin

CD22 is found in more than 90% patients with B-ALL [Citation70]. Inotuzumab Ozogamicin is an anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic agent, leading to cell apoptosis through internalization [Citation71–75].

The global phase 3 INO-VATE trial (NCT01564784) compared the efficacy of single-agent Inotuzumab Ozogamicin against standard intensive chemotherapy in patients with CD22-positive relapsed or refractory B-ALL. In each cycle, Inotuzumab Ozogamicin was administrated 0.8–0.5 mg/m2 on day 1 and 0.5 mg/m2 on day 8 and day 15 for up to 6 cycles. Those treated by Inotuzumab Ozogamicin were associated with a significantly higher rate of CR (80.7%: 29.4%; p < 0.001) and a longer CR duration (4.6 months: 3.1 months; P = 0.03). Among patients who achieved CR, 78.4% were MRD negative in the Inotuzumab Ozogamicin group versus 28.1% in the standard-therapy group (P < 0.001). Survival analysis also documented the superiority of Inotuzumab Ozogamicin with median progression-free survival (PFS) improved from 1.8 months to 5.0 months (HR: 0.45; p < 0.001) and median OS improved from 6.7 months to 7.7 months (HR: 0.77; P = 0.04) [Citation76]. Results were further confirmed in the long-term survival follow-up with a higher 2-year OS rate in the Inotuzumab Ozogamicin group (22.8%: 10.0%; HR: 0.75; P = 0.0105) [Citation77]. In the subset analysis by age cohort, although patients < 55 years old were associated with a longer median OS (8.6: 5.6 months; HR:0.610) compared to those ≥55 years old, no significant difference of CR/CRi rates (75%: 70%; P = 0.24), MRD-negativity rate (76%: 79%; P = 0.64), duration of remission (DOR) (5.4 months: 4.7 months; HR = 0.748; P = 0.0934), PFS (5.0 months: 4.9 months, P = 0.1010) or incidences of any-grade treatment-emergent adverse events (TEAEs) (99%: 100%) was seen between the two age groups, suggesting Inotuzumab Ozogamicin could be well tolerated by the elderly [Citation78]. It was noteworthy that liver damage of any degree occurred in about half of the patients (51%) in Inotuzumab Ozogamicin group, compared to 34% in standard care group. Sinusoidal obstruction syndrome (SOS) was more frequently observed in the Inotuzumab Ozogamicin group (13%: <1%) as well, thus liver-related adverse events should not be neglected during and after the treatment [Citation79]. Trials on whether a lower dose of Inotuzumab Ozogamicin can have a similar effect while reducing its treatment-emergent hepatotoxicity are still ongoing. (e.g. NCT03677596) A pooled analysis investigated the outcome of 101 patients who proceeded to allo-HSCT after attaining CR with Inotuzumab Ozogamicin from the INO-VATE trial and another earlier phase 1/2 trial (NCT01363297) [Citation80]. The most favorable 2-year survival laid in patients without previous HSCT or extra salvage treatment as a ratio of 51% [Citation81].

In a retrospective study, pediatric patients with relapsed or refractory ALL were likewise well responded to Inotuzumab Ozogamicin, with 67% of CR/CRi rates. Among those in remission, 71% were MRD negative. Although SOS only occurred in the post-HSCT population, the incidence of which was much higher than that of in the INO-VATE trial (52%: 22%) [Citation82]. Prospective studies are still ongoing (eg. NCT02981628, NCT03094611) to further assess the use of Inotuzumab Ozogamicin in children.

Unlike pediatric patients, adults and the elderly were characterized by poor tolerance to chemotherapy according to past experience. In order to improve this situation, a single-arm, phase 2 study (NCT01371630) was performed to explore the effect of Inotuzumab Ozogamicin plus mini-hyper-CVD. Mini-hyper-CVD, a modified version of standard hyper-CVAD with lower dose, referred to cyclophosphamide and dexamethasone reduced to 50%, methotrexate reduced to 25% and no anthracycline. In 59 R/R ALL patients aged 18–87 years, 78% responded, of whom 82% were negative for MRD. The 1-year RFS and OS rates were 40% and 46%, respectively [Citation83]. Encouraging results were also reported in patients with newly-diagnosed Ph- ALL aged 60 years and over. All but one patient (98%) achieved responses, and estimated 3-year EFS and OS were 49% (32–64) and 56% (39–70), respectively [Citation84].

4. Conclusion and discussion

The last decade has witnessed exciting survival improvements in ALL patients due to the progress made in monoclonal antibodies. Common targeted antigens include CD20、CD19 and CD22. Rituximab is a chimeric monoclonal antibody against CD20. For patients expressing at least 20% of CD20 and younger than 60 years old, combining Rituximab with hyper-CVAD regimen prolonged their CR duration and OS. Based on the positive response in treating adult patients, now a CCCG Relapsed ALL 2017 Study assesses the remission rate and MRD response in pediatric group treated with Rituximab and Bortezomib, a proteasome inhibitor [Citation85]. Because the course of induction often goes with an increased level of CD20, the use of another anti-CD20 monoclonal antibody, Ofatumumab, which makes AYAs’ 4-year EFS and OS comparable to those treated with pediatric-inspired regimens may expand the indication to patients with at least 1% of CD20 expression. Blinatumomab, a bispecific T-cell binding antibody, has been approved by FDA for patients with R/R B-ALL, as well as patients with morphologic remission but MRD+ ALL. We suggest it to be an effective bridging approach to eradicate MRD before transplantation, and serves as a promising choice to achieve long-term survival for patients ineligible to undergo transplantation. Ongoing clinical trials include how well Blinatumomab works in treating patients with MRD [Citation86] and how effective Blinatumomab combines with Nivolumab (PD-1 checkpoint inhibitor) or Ipilimumab (CTLA-4 checkpoint inhibitor) in patients with R/R ALL [Citation87,Citation88]. Inotuzumab Ozogamicin is an anti-CD22 monoclonal antibody conjugated to a cytotoxic agent called calicheamicin. Among patients with CD22+ R/R B-ALL, encouraging results have been seen in all ages, so single-agent Inotuzumab Ozogamicin is recommended for children, adults and the elderly. Inotuzumab Ozogamicin plus mini-hyper-CVD chemotherapy is recommended for patients aged 60 years and over with newly-diagnosed Ph− ALL, but hepatotoxicity of any degree should be worthy of our attention at any time. Phase II trials evaluate Inotuzumab Ozogamicin in both pediatric and adult patients with detectable MRD are underway [Citation89,Citation90]. The combination of two different monoclonal antibodies, such as Blinatumomab and Inotuzumab Ozogamicin [Citation91,Citation92], and the development of new antibodies include antibody to CD20, CD19, CD123, and bispecific antibody to CD19 / CD3 are on progress [Citation93–96]. Ongoing clinical trials mentioned above are listed in . In conclusion, the rise of monoclonal antibodies provides doctors with more options, but also brings new challenges in how to choose the most suitable therapy for each patient and achieve Individualized precision treatment.

Table 2. Ongoing trials focus on the future direction of monoclonal antibodies.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Key Medical of Jiangsu Province [grant number ZDXKB2016020] and Guo Qinglong 2016 Nanjing Emerging Industry Guidance Special Fund [grant number YY2016120701].

References

  • Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet. 2020;395(10230):1146–1162.
  • Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(14):1663–1669.
  • Pui C-H, Yang JJ, Hunger SP, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol. 2015;33(27):2938–2U24.
  • Jabbour E, O'Brien S, Konopleva M, et al. New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia. Cancer. 2015;121(15):2517–2528.
  • Pulte D, Jansen L, Gondos A, et al. Survival of adults with acute lymphoblastic leukemia in Germany and the United States. PLoS One. 2014;9:1.
  • Sive JI, Buck G, Fielding A, et al. Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial. Br J Haematol. 2012;157(4):463–471.
  • Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29:532–543.
  • Ribera JM, Oriol A, Sanz MA, et al. Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96. J Clin Oncol. 2008;26:1843–1849.
  • Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009;27:911–918.
  • DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia. 2015;29:526–534.
  • Huguet F, Chevret S, Leguay T, et al. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018;36(24):2514.
  • Gokbuget N, Hoelzer D. Treatment with monoclonal antibodies in acute lymphoblastic leukemia: current knowledge and future prospects. Ann Hematol. 2004;83(4):201–205.
  • Bene MC, Nebe T, Bettelheim P, et al. Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10. Leukemia. 2011;25(4):567–574.
  • Maury S, Huguet F, Leguay T, et al. Adverse prognostic significance of CD20 expression in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. Haematologica. 2010;95(2):324–328.
  • Thomas DA, O'Brien S, Jorgensen JL, et al. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood. 2009;113(25):6330–6337.
  • Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–242.
  • Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23(28):7013–7023.
  • Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18):4079–4088.
  • Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975–980.
  • Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106(7):1569–1580.
  • Oriol A, Ribera J-M, Bergua J, et al. High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma – comparison of results in human immunodeficiency virus-infected and noninfected patients. Cancer. 2008;113(1):117–125.
  • Hoelzer D, Walewski J, Doehner H, et al. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood. 2014;124(26):3870–3879.
  • Ribrag V, Koscielny S, Bosq J, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt’s lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10036):2402–2411.
  • Chevallier P, Pigneux A, Robillard N, et al. Rituximab for the treatment of adult relapsed/refractory CD20 positive B-ALL patients: a pilot series. Leuk Res. 2012;36(3):311–315.
  • Thomas DA, O'Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010;28(24):3880–3889.
  • Maury S, Chevret S, Thomas X, et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016;375(11):1044–1053.
  • Teeling JL, Mackus WJM, Wiegman LJJM, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006;177(1):362–371.
  • Cheson BD. Ofatumumab, a novel anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. J Clin Oncol. 2010;28(21):3525–3530.
  • Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385(9980):1873–1883.
  • Wierda WG, Padmanabhan S, Chan GW, et al. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011;118(19):5126–5129.
  • Gaipa G, Basso G, Maglia O, et al. Drug-induced immunophenotypic modulation in childhood ALL: implications for minimal residual disease detection. Leukemia. 2005;19:49–56.
  • Borowitz MJ, Pullen DJ, Winick N, et al. Comparison of diagnostic and relapse flow cytometry phenotypes in childhood acute lymphoblastic leukemia: implications for residual disease detection: a report from the Children’s Oncology Group. Cytometry B Clin Cytom. 2005;68:18–24.
  • Jabbour E, Richard-Carpentier G, Sasaki Y, et al. Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial. Lancet Haematology. 2020;7(7):E523–EE33.
  • Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019;133(14):1548–1559.
  • Huguet F, Chevret S, Leguay T, et al. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018;36(24):2514.
  • Toft N, Birgens H, Abrahamsson J, et al. Results of NOPHO ALL2008 treatment for patients aged 1–45 years with acute lymphoblastic leukemia. Leukemia. 2018;32(3):606–615.
  • Larsen EC, Devidas M, Chen S, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children’s Oncology Group Study AALL0232. J Clin Oncol. 2016;34(20):2380–U129.
  • Rytting ME, Jabbour EJ, Jorgensen JL, et al. Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Munster, in adolescents and young adults with acute lymphoblastic leukemia, and comparison to the hyper-CVAD regimen. Am J Hematol. 2016;91(8):819–823.
  • DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia. 2015;29(3):526–534.
  • Ribera J-M, Oriol A, Sanz M-A, et al. Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the programa espanol de tratamiento en hematologia pediatric-based protocol ALL-96. J Clin Oncol. 2008;26(11):1843–1849.
  • Hoffmann P, Hofmeister R, Brischwein K, et al. Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct. Int J Cancer. 2005;115(1):98–104.
  • Raponi S, De Propris MS, Intoppa S, et al. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymph. 2011;52(6):1098–1107.
  • Topp MS, Goekbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66.
  • Topp MS, Gokbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134–U363.
  • Kantarjian H, Stein A, Goekbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–847.
  • Rambaldi A, Huguet F, Zak P, et al. Blinatumomab consolidation and maintenance therapy in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia. Blood Adv. 2020;4(7):1518–1525.
  • Beldjord K, Chevret S, Asnafi V, et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood. 2014;123(24):3739–3749.
  • Ravandi F, Jorgensen JL, O'Brien SM, et al. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia. Br J Haematol. 2016;172(3):392–400.
  • Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3:7.
  • Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944–950.
  • Goekbuget N, Kneba M, Raff T, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120(9):1868–1876.
  • Giebel S, Labopin M, Socie G, et al. Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the acute leukemia working party of the European society for blood and marrow transplantation. Haematologica. 2017;102(1):139–149.
  • Goekbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522–1531.
  • Jen EY, Xu Q, Schetter A, et al. FDA approval: blinatumomab for patients with B-cell precursor acute lymphoblastic leukemia in morphologic remission with minimal residual disease. Clin Cancer Res. 2019;25(2):473–477.
  • Goekbuget N, Zugmaier G, Dombret H, et al. Curative outcomes following blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2020;61(11):2665–2673.
  • Jabbour EJ, Goekbuget N, Kantarjian HM, et al. Transplantation in adults with relapsed/refractory acute lymphoblastic leukemia who are treated with blinatumomab from a phase 3 study. Cancer. 2019;125(23):4181–4192.
  • Clesham K, Rao V, Bartram J, et al. Blinatumomab for infant acute lymphoblastic leukemia. Blood. 2020;135(17):1501–1504.
  • Pieters R, De Lorenzo P, Ancliffe P, et al. Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the interfant-06 protocol: results from an international phase III randomized study. J Clin Oncol. 2019;37(25):2246.
  • Driessen EMC, de Lorenzo P, Campbell M, et al. Outcome of relapsed infant acute lymphoblastic leukemia treated on the interfant-99 protocol. Leukemia. 2016;30(5):1184–1187.
  • Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia – results of the prospective multicenter LALA-94 trial. Blood. 2002;100(7):2357–2366.
  • Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood. 2007;109(9):3676–3678.
  • Bassan R, Rossi G, Pogliani EM, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: northern Italy leukemia group protocol 09/00. J Clin Oncol. 2010;28(22):3644–3652.
  • Tanguy-Schmidt A, Rousselot P, Chalandon Y, et al. Long-term follow-up of the Imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant. 2013;19(1):150–155.
  • Brissot E, Labopin M, Beckers MM, et al. Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia. Haematologica. 2015;100(3):392–399.
  • Carpenter PA, Johnston L, Fernandez HF, et al. Posttransplant feasibility study of nilotinib prophylaxis for high-risk Philadelphia chromosome positive leukemia. Blood. 2017;130(9):1170–1172.
  • Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35(16):1795.
  • Rambaldi A, Ribera J-M, Kantarjian HM, et al. Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia. Cancer. 2020;126(2):304–310.
  • Couturier M-A, Thomas X, Raffoux E, et al. Blinatumomab plus ponatinib for relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia in adults. Leuk Lymphoma. 2021;62(3):620–629.
  • King AC, Pappacena JJ, Tallman MS, et al. Blinatumomab administered concurrently with oral tyrosine kinase inhibitor therapy is a well-tolerated consolidation strategy and eradicates measurable residual disease in adults with Philadelphia chromosome positive acute lymphoblastic leukemia. Leuk Res. 2019;79:27–33.
  • Shah NN, Stevenson MS, Yuan CM, et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr Blood Cancer. 2015;62(6):964–969.
  • Shor B, Gerber H-P, Sapra P. Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies. Mol Immunol. 2015;67(2):107–116.
  • Bouchard H, Viskov C, Garcia-Echeverria C. Antibody-drug conjugates – a new wave of cancer drugs. Bioorg Med Chem Lett. 2014;24(23):5357–5363.
  • Haso W, Lee DW, Shah NN, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121(7):1165–1174.
  • de Vries JF, Zwaan CM, De Bie M, et al. The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells. Leukemia. 2012;26(2):255–264.
  • DiJoseph JF, Armellino DC, Boghaert ER, et al. Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood. 2004;103(5):1807–1814.
  • Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740–753.
  • Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125(14):2474–2487.
  • Jabbour EJ, DeAngelo DJ, Stelljes M, et al. Efficacy and safety analysis by age cohort of Inotuzumab Ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE. Cancer. 2018;124(8):1722–1732.
  • Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematology. 2017;4(8):E387–EE98.
  • DeAngelo DJ, Stock W, Stein AS, et al. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. Blood Advances. 2017;1(15):1167–1180.
  • Marks DI, Kebriaei P, Stelljes M, et al. Outcomes of allogeneic stem cell transplantation after Inotuzumab Ozogamicin treatment for relapsed or refractory acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2019;25(9):1720–1729.
  • Bhojwani D, Sposto R, Shah NN, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019;33(4):884–892.
  • Jabbour E, Ravandi F, Kebriaei P, et al. Salvage chemoimmunotherapy with Inotuzumab Ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: A phase 2 clinical trial. JAMA Oncol. 2018;4(2):230–234.
  • Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018;19(2):240–248.
  • Clinicaltrials.gov. Chinese Children Cancer Group Relapsed Acute Lymphoblastic Leukemia 2017 Study. Available at: www.clinicaltrials.gov (NCT04224571).
  • Clinicaltrials.gov. Phase II Study of Blinatumomab in Patients With B-Cell Lineage Acute Lymphocytic Leukemia With Positive Minimal Residual Disease. Available at: www.clinicaltrials.gov (NCT02458014).
  • Clinicaltrials.gov. A Phase 2 Study of Blinatumomab (NSC# 765986) in Combination With Nivolumab (NSC # 748726), a Checkpoint Inhibitor of PD-1, in B-ALL Patients Aged ≥ 1 to &lt; 31 Years Old With First Relapse. Available at: www.clinicaltrials.gov (NCT04546399).
  • Clinicaltrials.gov. A Phase 1 Study of Blinatumomab in Combination With Checkpoint Inhibitor(s) of PD-1 (Nivolumab) or Both PD-1 (Nivolumab) and CTLA-4 (Ipilimumab) in Patients With Poor-Risk, Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia. Available at: www.clinicaltrials.gov (NCT02879695).
  • Clinicaltrials.gov. Inotuzumab Ozogamicin for Children With MRD Positive CD22+ Lymphoblastic Leukemia. Available at: www.clinicaltrials.gov (NCT03913559).
  • Clinicaltrials.gov. Phase II Study of Inotuzumab Ozogamicin in Patients With B-Cell Lineage Acute Lymphocytic Leukemia With Positive Minimal Residual Disease. Available at: www.clinicaltrials.gov (NCT03441061).
  • Clinicaltrials.gov. A Phase II Study of Inotuzumab Ozogamicin Followed by Blinatumomab for Ph-Negative CD22-Positive B-Lineage Acute Lymphoblastic Leukemia in Newly Diagnosed Older Adults or Adults With Relapsed or Refractory Disease. Available at: www.clinicaltrials.gov (NCT03739814).
  • Clinicaltrials.gov. Phase II Study of the Hyper-CVAD Regimen in Sequential Combination With Blinatumomab With or Without Inotuzumab Ozogamicin as Frontline Therapy for Adults With B-Cell Lineage Acute Lymphocytic Leukemia. Available at: www.clinicaltrials.gov (NCT02877303).
  • Clinicaltrials.gov. A Phase I/II Study to Evaluate the Safety and Anti-Tumor Activity of ADCT-602 Targeting CD22 in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. Available at: www.clinicaltrials.gov (NCT03698552).
  • Clinicaltrials.gov. Open-label Multicenter Non-comparative Clinical Trial of Tolerability, Safety, Pharmacokinetics and Pharmacodynamics of GNR-084 in Patients With Refractory or Relapse Acute Lymphoblastic B-cell Precursor Leukemia in Sequential Cohorts With Dose Escalation. Available at: www.clinicaltrials.gov (NCT04601584).
  • Clinicaltrials.gov. Phase Ⅱ Clinical Trial of CNCT19 Cell Injection in the Treatment of CD19 Positive Relapsed or Refractory Acute Lymphoblastic Leukemia. Available at: www.clinicaltrials.gov (NCT04684147).
  • Clinicaltrials.gov. A Phase 1 Trial to Evaluate the Safety of Single Agent Flotetuzumab in Advanced CD123-Positive Hematological Malignancies. Available at: www.clinicaltrials.gov (NCT04681105).