Abstract

With modern intensive combination polychemotherapy, the complete response (CR) rate in adults with acute lymphoblastic leukemia (ALL) is 80% to 90%, and the cure rate is 40% to 50%. Hence, there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy. ALL leukemic cells express several surface antigens amenable to target therapies, including CD20, CD22, and CD19. Monoclonal antibodies target these leukemic surface antigens selectively and minimize off-target toxicity. When added to frontline chemotherapy, rituximab, an antibody directed against CD20, increases cure rates of adults with Burkitt leukemia from 40% to 80% and those with pre-B ALL from 35% to 50%. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has resulted in marrow CR rates of 55% and a median survival of 6 to 7 months when given to patients with refractory-relapsed ALL. Blinatumomab, a biallelic T cell engaging the CD3-CD19 monoclonal antibody, also resulted in overall response rates of 40% to 50% and a median survival of 6.5 months in a similar refractory-relapsed population. Other promising monoclonal antibodies targeting CD20 (ofatumumab and obinutuzumab) or CD19 or CD20 and bound to different cytotoxins or immunotoxins are under development. Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation.

Introduction

The estimated annual incidence of acute lymphoblastic leukemia (ALL) is 6000 cases in the United States.1  The disease spans the age continuum, with ∼60% of cases diagnosed in patients under the age of 20 and 11% in patients >65 years of age.2  This makes the management of ALL complex, as patient and leukemic factors have to be considered when designing a therapeutic plan.

Multiagent combination chemotherapy regimens for the treatment of ALL are considered a cancer success story in the pediatric setting.3  Pioneered >5 decades ago, optimization of drug combinations, doses, and sequences has offered patients who once had a dismal prognosis a cure rate of 90%.4,5  For adults, the same magnitude of success has not been realized using similar strategies. These regimens produce high complete remission (CR) rates of 80% to 90%, but the cure rates are 40% to 50%.6,7  Incorporation of targeted agents has improved survival and cure rates in adult ALL subsets.7-9 

Recent data have suggested that adults up to the age of 39 years may benefit from pediatric-inspired chemotherapy regimen compared with historical adult regimens.10,11  This may be because of the modifications in the common adult ALL regimens shifting away from the backbone ALL therapies applied in pediatric leukemias. However, the hyper-cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) regimen, which kept such principles but eliminated or reduced asparaginase exposure, showed similar remission duration and survival outcomes compared with the pediatric-inspired regimen in similar patient populations.12 

Cytotoxic chemotherapy results are modest in the setting of refractory-relapsed ALL, producing CR rates of 30% to 40% in first salvage and 10% to 20% in later salvages. Few patients can be bridged to allogeneic stem cell transplantation (ASCT): 5% to 10% in some studies but as high as 30% to 40% in German trials.13-15  This bridging to ASCT offers a chance of long-term remissions and cures (<20-30%).

One of the most exciting group of compounds under investigation in ALL is monoclonal antibodies that target leukemic blast surface antigens (Figure 1). Monoclonal antibodies are designed to bind to a specific abundant target on leukemic cells but less expressed on normal cells. Monoclonal antibodies work through a number of mechanisms, including antibody-dependent cytotoxicity, complement-dependent cytotoxicity, and direct induction of apoptosis. If a target is known to internalize on binding, potent cytotoxins can be conjugated to the antibody portion, producing an additional mechanism for leukemic-targeted killing. ALL blasts targets studied most thoroughly to date include CD19, CD20, CD22, and CD52 (Table1). The anti-CD20 antibody rituximab has produced encouraging results as a component of the initial ALL therapy of Burkitt ALL and CD20-positive pre-B ALL.8,9  This observation is interesting in itself, because single-agent rituximab has no activity in ALL. Other monoclonal antibodies targeting CD19 and CD22 are under evaluation in clinical trials of refractory-relapsed ALL. The promising results led to combining the new monoclonal antibodies with standard chemotherapy in ALL salvage and frontline regimens. Combination of different monoclonal antibodies may in the future replace components of contemporary chemotherapy regimens. Herein, we review the current status of the results achieved thus far with existing and newer monoclonal antibodies in ALL.

Figure 1

Schema of different monoclonal antibodies.

Figure 1

Schema of different monoclonal antibodies.

Table 1

Targeted therapies for ALL

TherapyDescription
CD20  
 Rituximab When added to conventional chemotherapy has been shown to improve survival in younger adults 
 Ofatumumab Binds to a different epitope than rituximab, which may allow it to overcome rituximab-resistant disease 
 Obinutuzumab Novel glycoengineered type II CD20 monoclonal antibody superior to rituximab and ofatumumab in the induction of direct cell death. 
CD19  
 SAR3419 Conjugated to a synthetic maytansinoid that is release intracellularly after antigen internalization 
 SGN-CD19A Humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent. On internalization, it binds to tubulin and induces G2/M arrest and apoptosis 
 Blinatumomab Bispecific antibody that redirects cytotoxic T cells to cells that express CD19 
CD22  
 Epratuzumab Studied as part of combination therapy in adults and children with modest activity 
 Epratuzumab-SN38 Antibody conjugated to a topoisomerase I inhibitor to enhance cell killing potential 
 Inotuzumab ozogamicin Antibody conjugated to the cytotoxin calicheamicin 
 Moxetumomab Antibody conjugated to bacterial or plant toxin 
CD52  
 Alemtuzumab Antibody that has only displayed little activity in B- and T-cell disease 
TherapyDescription
CD20  
 Rituximab When added to conventional chemotherapy has been shown to improve survival in younger adults 
 Ofatumumab Binds to a different epitope than rituximab, which may allow it to overcome rituximab-resistant disease 
 Obinutuzumab Novel glycoengineered type II CD20 monoclonal antibody superior to rituximab and ofatumumab in the induction of direct cell death. 
CD19  
 SAR3419 Conjugated to a synthetic maytansinoid that is release intracellularly after antigen internalization 
 SGN-CD19A Humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent. On internalization, it binds to tubulin and induces G2/M arrest and apoptosis 
 Blinatumomab Bispecific antibody that redirects cytotoxic T cells to cells that express CD19 
CD22  
 Epratuzumab Studied as part of combination therapy in adults and children with modest activity 
 Epratuzumab-SN38 Antibody conjugated to a topoisomerase I inhibitor to enhance cell killing potential 
 Inotuzumab ozogamicin Antibody conjugated to the cytotoxin calicheamicin 
 Moxetumomab Antibody conjugated to bacterial or plant toxin 
CD52  
 Alemtuzumab Antibody that has only displayed little activity in B- and T-cell disease 

CD20-directed therapy

Rituximab

The surface antigen CD20 is found on ∼30% to 50% of the precursor B-cell lymphoblasts.16,17  Rituximab is a chimeric monoclonal antibody originally developed and approved for the treatment of non-Hodgkin lymphoma.18  Several studies have reported that the addition of rituximab to chemotherapy has improved cure rates in Burkitt ALL (Table 2).8,19,20  Two studies have shown the same for pre-B ALL.9,19 

Table 2

Activity of rituximab in patients with Burkitt leukemia

Percent survival
MDACC9 Germany19 CALGB20 
Therapy 4 years 3 years 4 years 
Chemotherapy 50 50 52 
Chemotherapy + rituximab 77 79 78 
Percent survival
MDACC9 Germany19 CALGB20 
Therapy 4 years 3 years 4 years 
Chemotherapy 50 50 52 
Chemotherapy + rituximab 77 79 78 

Thomas et al evaluated the addition of rituximab to the hyper-CVAD regimen in newly diagnosed patients with Philadelphia-negative, CD20-positive ALL.8  Two doses of rituximab were given with each of the first 4 cycles of intensive chemotherapy (total of 8 doses of rituximab). Rituximab was also incorporated into early and late intensification cycles (months 6 and 18 of maintenance therapy). Among patients <60 years of age, the addition of rituximab improved CR duration and 3-year survival rates (75% vs 47%; P = .003). The German Multicenter Study Group for ALL also reported an improvement in 5-year survival rates with the addition of rituximab to standard induction and consolidation chemotherapy in patients who are <55 years of age.19 

Most protocols have restricted rituximab use to patients whose leukemic blast cells exhibit CD20 expression of >20%. Pretreatment with corticosteroids (routinely used in ALL therapy) also upregulates CD20 expression on leukemia cells.21  Studies evaluating combined immunochemotherapy among patients with pre-B ALL and CD20 positivity of 0% to 20% are warranted. Central nervous system (CNS) relapse is common in ALL. Patients who develop CNS disease have historically a poor prognosis. Phase 1 studies have established the safety of intraventricular rituximab in patients with primary CNS and intraocular lymphoma.22  An ongoing phase 1/2 study is testing the effectiveness of intraventricular rituximab in patients with ALL CNS relapse.23 

Rituximab is generally well tolerated.18  The most common adverse events are infusion related and occur most frequently during or shortly after the first infusion. About 95% of these adverse reactions are mild or moderate and resolve completely after temporary interruption of the infusion. Rare cases of severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy were reported.18 

Ofatumumab

Ofatumumab is a second-generation anti-CD20 monoclonal antibody that binds to a site different than rituximab.24  Ofatumumab targets a membrane proximal small-loop epitope on the CD20 molecule and is more potent than rituximab. In chronic lymphocytic leukemia (CLL), ofatumumab has shown significant activity after previous rituximab exposure.25  In a phase 2 study in pre-B CD20 ALL, the combination of hyperfractionated-CVAD (HCVAD) with ofatumumab was found to be highly effective.26  Twenty-five patients with de novo pre-B CD20-positive ALL were treated. Ofatumumab was given as 2 g twice per course in the first 4 courses. The rates of CR and minimal residual disease (MRD; by 6-color multiparameter flow) negativity were both 96%. With a median follow-up of 14 months, the 1-year progression-free and overall survival rates were 94% and 92%, respectively.26 

Obinutuzumab

Obinutuzumab is a novel glycoengineered type II CD20 monoclonal antibody that is superior to rituximab and ofatumumab in the induction of direct cell death.27  In patients with untreated CLL, treatment with obinutuzumab and chlorambucil, compared with chlorambucil alone, prolonged survival (P = .002).28  Treatment with obinutuzumab and chlorambucil, compared with rituximab and chlorambucil, resulted in prolongation of progression-free survival (P < .001) and in higher rates of complete response and molecular response.28  Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased. Investigation of obinutuzumab in patients with CD20-positive ALL is warranted.

CD19-directed therapy

CD19 is ubiquitously expressed on B cells. Its expression is continuous from very early stages and throughout differentiation.29  The antigen is also known to internalize on binding of antibody, making it an attractive target for immunoconjugate therapy.

SAR3419

SAR3419 is a humanized monoclonal antibody linked to a semisynthetic maytansinoid compound, an antimitotic agent that binds to the same site on tubulin as vincristine.30  Maytansinoids are far more potent than the vinca alkaloids, and development of these compounds as anticancer therapies was halted early because of excessive systemic toxicity. Selective delivery of very small doses of a maytansinoid to malignant tissue (eg, leukemia cells), via linkage to an antibody, has renewed interest in their therapeutic potential. In preclinical models, SAR3419 significantly delayed the progression of 4 of 4 CD19-positive B-cell precursor ALL and 3 of 3 mixed lineage leukemia xenografts and induced objective responses in all but 1 xenograft, but was ineffective against T-lineage ALL xenografts.31  A phase 1 study of SAR3419 was conducted in patients with relapsed and/or refractory B-cell lymphoma to determine the maximally tolerated dose (MTD).32  The dose-limiting toxicity was reversible severe blurred vision, which was associated with epithelial corneal changes. The MTD was 160 mg/m2 intravenously every 3 weeks. Among 39 patients treated, 74% had reductions in tumor size; 1 patient achieved CR. A phase 2 study in adults with relapsed ALL was completed.33 

SGN-CD19A

SGN-CD19A is a novel antibody-drug conjugate composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. On binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells.34  In a phase 1 dose finding study, 13 patients with relapsed or refractory B-lineage ALL (n = 9) and highly aggressive lymphoma (n = 4) received SGN-CD19A on days 1 and 8 of every 21-day cycle.35  The starting dose was 0.3 mg/kg up and was escalated to 1.3 mg/kg per dose. No MTD was reached thus far. Across all dose levels, 1 of the 8 (12.5%) evaluable patients with ALL achieved CR. Adverse events of any grade were nausea (64%), fever (55%), chills (36%), and headache (27%). The study is ongoing. A second trial is evaluating SGN-CD19A every 3 weeks in aggressive B-cell non-Hodgkin lymphoma.

Blinatumomab

The bispecific T-cell engaging antibody blinatumomab represents the first agent in a class that redirects host T cells to cell surface antigen-expressing cancer cells. Blinatumomab contains the variable domains of a CD19 antibody and a CD3 antibody, which are joined by a nonimmunogenic linker.35  On binding to CD19, the cytotoxic T cells become activated and induce cell death via the pore-forming perforin system. The drug was initially administered as an intermittent infusion 2 to 3 times weekly, but lack of activity and serious neurologic toxicity caused the schedule of administration to be abandoned.35  Based on the short half-life of the drug and the mechanism of action, continuous infusion over several weeks was investigated. This drastically improved the activity of the drug, particularly in ALL, and minimized adverse effects.

MRD.

The first study with blinatumomab used as continuous infusion evaluated its potential role in eradicating MRD.35  MRD positivity in ALL almost universally heralds systemic relapse and confers poor prognosis. Patients treated in this study were in hematologic and morphologic CR, but had persistent or reappearing MRD during consolidation chemotherapy. Blinatumomab was given at a dose of 15 μg/m2 per day as a continuous infusion for 28 days every 6 weeks.36  After completing 1 cycle, responding patients could receive up to 3 additional consolidation cycles or proceed to ASCT if a donor was available. MRD conversion after 1 cycle was observed in 16 of 20 evaluable patients (80%). In a long-term follow-up update (median observation time, 33 months), 12 of the 20 patients remained in CR. The estimated 3-year relapse-free survival was 60%.37  Nine patients underwent ASCT, but interestingly, nontransplanted patients had similar favorable outcome compared with the transplant group. Most relapses after blinatumomab treatment occurred early, within 7 months of the start of therapy.

Within hours after start of blinatumomab infusion, a rapid T-cell redistribution was observed: after a rapid reduction, T cells recovered immediately to pretreatment levels and expanded over baseline during the further course of the first treatment cycle. This pattern was observed in 8 of 17 evaluable patients. Although generally both CD4+ and CD8+ T-cell subpopulations participated in the increase, the subset of effector memory T cells accounted for the major portion of expanded cells, whereas the naive T-cell subset remained essentially unchanged. This long-lasting effect of blinatumomab may be caused by the amplification of cytotoxic effector T cells induced by the anti-CD3 arm that corresponds to the proliferation induced by the cognate interaction of the specific T-cell receptor with infected target cells.37 

Relapsed and refractory disease.

Blinatumomab was subsequently studied in patients with active systemic ALL relapse. The results of this ongoing trial were updated recently (Table 3).38,39  Three dose levels were explored, all involving blinatumomab administration as a continuous infusion for 28 days every 6 weeks. The overall response rate (ORR; CR or CR with incomplete count recovery) within 2 cycles of therapy was 69%. The estimated median survival was 9.8 months.38  The final dose selected for future studies was 5 μg/m2 per day during week 1 and 15 μg/m2 per day during the following 3 weeks. In a confirmatory open-label, single-arm, multicenter phase 2 study in 189 patients with relapsed-refractory disease, the ORR was 43%, with 80% of the responses occurring within cycle 1. The median response duration and overall survival were 9 and 6 months, respectively (Table 3).39 

Table 3

Activity of blinatumomab in patients with relapsed/refractory ALL

ParameterN (%)
Pivotal study, n = 36Confirmatory study, n = 189
Response   
 CR 15 (42) 62 (33) 
 CR with incomplete count recovery 10 (28) 19 (10) 
 All responders 25 (69) 81 (43) 
Salvage status   
 Salvage 1 11 (31) 38 (20) 
 Salvage 2+ 10 (28) 151 (80) 
Median survival (months) 9.8 6.1 
ParameterN (%)
Pivotal study, n = 36Confirmatory study, n = 189
Response   
 CR 15 (42) 62 (33) 
 CR with incomplete count recovery 10 (28) 19 (10) 
 All responders 25 (69) 81 (43) 
Salvage status   
 Salvage 1 11 (31) 38 (20) 
 Salvage 2+ 10 (28) 151 (80) 
Median survival (months) 9.8 6.1 

The toxicity profile of blinatumomab has been largely consistent with historical studies, with fever, chills, and hypogammaglobulinemia occurring most frequently. Tremor, headache, and other mental status changes (eg, confusion) have been reported. Fever, chills, and other constitutional symptoms are thought to be caused by a cytokine release syndrome that occurs shortly after the start of therapy and are reduced with the use of steroids (eg, dexamethasone 8-24 daily ×2-3 days). The adverse effects coincided with a rapid rise in activated T cells after blinatumomab initiation, essentially confirming the hypothesis.40  Serious adverse events were uncommon, but seizures have been observed in both the MRD and the active disease studies. Corticosteroids before the first dose and before dose escalation ameliorate some of the toxicities.

Blinatumomab is currently being assessed in a phase 3 trial in patients with ALL in first or second relapse who are randomized to either blinatumomab or an investigator’s choice chemotherapy regimen and in a phase 2 study in patients with relapsed Philadelphia-positive ALL.

CD22-directed therapy

CD22 is expressed on leukemic blasts in >90% of patients with ALL.18  CD22 is rapidly internalized on antibody binding.41  Receptor internalization makes it an attractive target for monoclonal antibodies conjugated to cytotoxic compounds. Possible mechanisms of action of anti-CD22 antibodies include antibody-dependent cytotoxicity, modulation of B-cell signaling, and inhibition of proliferation.42 

Epratuzumab

Epratuzumab, an unconjugated antibody directed against CD22, was studied in pediatric relapsed ALL.43  Patients received a reduction phase with single agent epratuzumab administered twice weekly for 2 weeks, followed by standard salvage chemotherapy combined with the antibody. With single-agent epratuzumab, most patients had stable disease, and only 1 of 15 had a partial response. Serious toxicities observed included 1 grade 4 seizure and 1 grade 3 transaminitis, neither of which occurred during the epratuzumab-only phase.

In adult ALL, the Southwest Oncology Group has conducted a phase 2 study evaluating epratuzumab combined with clofarabine plus cytarabine in 31 patients experiencing first or later relapse.44  Epratuzumab was given intravenously weekly for 4 doses starting on day 7 of therapy. Most patients were in first relapse (59%); 13% had received prior ASCT. Overall, 16 patients (52%) responded: 10 CRs and 6 CRs with incomplete recovery of neutrophils or platelets. The median survival was 5 months. Of the 16 responding patients, only 6 had MRD assessed. Of these, only 1 became MRD negative (<0.01%); this patient survived for 11 months. Although epratuzumab may have exhibited modest activity, the ideal modality for targeting CD22 might be through using antibody-conjugate therapy. Epratuzumab has recently been linked to the topoisomerase I inhibitor SN-38 and demonstrated activity against several B-cell leukemia and lymphoma cell lines.45 

Inotuzumab ozogamycin

The immunoconjugate directed at CD22 furthest along in development is inotuzumab ozogamicin. The antibody is linked to calicheamicin, a potent cytotoxic compound that induces double-strand DNA breaks.46  Initial studies in patients with lymphoma established an MTD of 1.8 mg/m2 intravenously given every 3 to 4 weeks, with reversible thrombocytopenia emerging as a frequent adverse effect.47  This led to a single institution phase 2 study in patients with relapsed-refractory ALL.48  The starting dose was 1.3 mg/m2 intravenously every 3 to 4 weeks for the first 3 patients; later patients received 1.8 mg/m2. Acetaminophen, diphenhydramine, and hydrocortisone were administered to prevent infusion reactions. Forty-nine patients were treated, 73% of whom received inotuzumab for salvage 2 or later. The ORR was 57%, and the median survival was 5.1 months (Table 4). Nearly half of the patients treated with inotuzumab were able to proceed to ASCT (n = 22), including 4 patients who were receiving their second ASCT. Survival was similar whether patients underwent subsequent ASCT or not. Transient fever and hypotension were the 2 most frequent nonhematologic adverse events and typically occurred shortly after the inotuzumab infusion. Liver function abnormalities were also observed but tended to be reversible. Serious toxicity in the transplant group included the development of veno-occlusive disease (VOD) in 5 patients (23%). Four of the 5 patients had received multiple alkylating agents in the transplant preparative regimen, including clofarabine, which may have predisposed them to VOD. Two of the 4 patients undergoing second ASCT developed VOD, suggesting this group of patients to be also at higher risk for VOD.49 

Table 4

Activity of inotuzumab ozogamicin in patients with relapsed/refractory ALL

ParameterN (%)
Single dose, n = 49Weekly, n = 40Overall, n = 89
Response    
 CR 9 (18) 8 (20) 17 (19) 
 CRp 16 (33) 13 (33) 29 (33) 
 CRi 3 (6) 3 (8) 6 (7) 
 PR 
 Resistant 18 (37) 14 (35) 32 (36) 
 Death <4 weeks 3 (6) 2 (5) 5 (6) 
Salvage    
 Salvage 1 13 (27) 16 (40) 29 (33) 
 Salvage 2+ 36 (73) 24 (60) 60 (67) 
Median survival (months) 5.0 9.5 6.2 
ParameterN (%)
Single dose, n = 49Weekly, n = 40Overall, n = 89
Response    
 CR 9 (18) 8 (20) 17 (19) 
 CRp 16 (33) 13 (33) 29 (33) 
 CRi 3 (6) 3 (8) 6 (7) 
 PR 
 Resistant 18 (37) 14 (35) 32 (36) 
 Death <4 weeks 3 (6) 2 (5) 5 (6) 
Salvage    
 Salvage 1 13 (27) 16 (40) 29 (33) 
 Salvage 2+ 36 (73) 24 (60) 60 (67) 
Median survival (months) 5.0 9.5 6.2 

CRi, bone marrow CR; PR, partial response.

To optimize the benefit:risk ratio of inotuzumab, a weekly dosing regimen was evaluated based on preclinical studies indicating that toxicity might be minimized while maintaining efficacy (Table 4).50  Inotuzumab was given at 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15, every 3 to 4 weeks. This is the same cumulative dose per course compared with single infusion inotuzumab every 3 to 4 weeks. With the weekly regimen, ORR was similar to the single-dose schedule (59% vs 57%). The median survival was 9.5 months. The weekly regimen was less toxic. Fever of any grade occurred in 29% of patients with a single dose compared with 9% with the weekly schedule. There was also significantly less hepatotoxicity with the weekly regimen, including the incidence of VOD after ASCT (7% vs 23%). Patients receiving inotuzumab in salvage 2 and beyond, those with high peripheral absolute blast count, and those with poor karyotype [complex; translocation (4; 11); and translocation (9; 22)] had a lower likelihood of response and shorter overall survival.

Measurements of inotuzumab levels were conducted at the end of infusion, 3 hours after the end of infusion, and on days 7 and 8. Patients who achieved a marrow CR had lower clearance rates and higher area under the curve levels compared with patients who did not respond. Higher inotuzumab peak levels were observed with single-dose inotuzumab, but inotuzumab peak levels did not correlate with response rates.

Additionally, 37 patients with relapsed/refractory ALL received weekly inotuzumab in a multicenter phase 1/2 study.51  Seventeen (46%) patients were in salvage 1, 9 (24%) in salvage 2, and 11 (30%) in salvage 3 or later. The CR and CR without count recovery rates were 79% (19 of 24) and 46% (6 of 13) in the dose expansion and dose escalation cohorts, respectively. Eighteen of the 19 patients in the dose escalation cohort and 4 of the 6 in the dose expansion cohort achieved MRD negativity.

A randomized trial comparing inotuzumab with physician’s choice of chemotherapy in patients with ALL in first and second salvage is ongoing.

Inotuzumab ozogamicin in combination with low-intensity chemotherapy

Given the promising results in the salvage studies, inotuzumab was evaluated in combination with chemotherapy. A group of patients with ALL who may particularly benefit from a more targeted regimen is elderly patients (age > 60 years). This group is predisposed to severe toxicity from conventional chemotherapy, which is associated with high mortality rate (30-35%) during consolidation maintenance in CR. Twenty-six older patients (median age, 67 years; range, 60-79 years) with newly diagnosed ALL were treated in a phase 2 study combining inotuzumab and low-intensity hyper-CVAD therapy.52  The regimen eliminated doxorubicin in induction, used cyclophosphamide and steroids at 50% of the dose of previous regimens, and reduced methotrexate to 250 mg/m2 on day 1 and cytarabine to 0.5 mg/m2 × 4 (days 2 and 3) of even courses. Inotuzumab 1.3 to 1.8 mg/m2 was given once with each of the first 4 courses. The ORR was 96% (CR, 79%; CR with incomplete platelet recovery [CRp], 17%). All patients with cytogenetic abnormalities achieved a complete cytogenetic response. All patients achieving response also had a negative MRD status, 75% of them after 1 cycle. The 1-year progression-free and overall survival rates were 86% and 81%, respectively. The 1-year survival rate was superior to previous results obtained with HCVAD ± rituximab in similar patient populations (1-year survival rates of 81% and 60%, respectively).

This combination was also assessed as a salvage therapy in 32 patients. The ORR was 70% (CR, 50%; CRp, 17%; marrow CR, 3%). The 6-month progression-free rates and OSSs were 81% and 65%, respectively.52 

Moxetumomab pasudotox and BL22

Immunotoxins are proteins that consist of 2 primary components: a targeting moiety for cell binding and a bacterial or plant toxin that is internalized and causes cell death. BL22 (CAT-3888) is an anti-CD22 immunotoxin composed of a variable fragment (Fv) derived from a monoclonal antibody directed toward CD22 and fused to a 38-kDa fragment of Pseudomonas aeruginosa exotoxin A (RFB4 [dsFv]-PE38).53  Following preclinical studies demonstrating the cytotoxic effect of BL22 against CD22+ cell lines and leukemic cells from patient samples, BL22 was also found to be highly active in phase 1/2 human studies in hairy cell leukemia.54  Wayne et al evaluated BL22 in a phase 1 study in childhood ALL. BL22 was administered at doses of 10 to 40 μg/kg every other day for 3 or 6 doses every 3 to 4 weeks. No dose-limiting toxicities were noted. Among 23 patients treated, 16 (70%) showed reductions of leukemic blasts; 4 patients had more than 2-log reductions of circulating blasts, and 4 patients had normalizations of peripheral blast counts. No objective CRs or partial responses were noted.55 

To improve the efficacy of BL22 in non–hairy cell leukemia tumors, further mutagenesis analysis was performed and resulted in the selection of an Fv with a higher binding affinity to surface CD22 by virtue of a slower off rate.56  This new compound, initially named high-affinity BL22 (HA22), was later renamed moxetumomab pasudodotox. In a phase 1 study, 21 children and young adolescents with relapsed-refractory ALL received moxetumomab pasudotox every other day for 6 doses.57  Cycles were repeated every 3 weeks. Grade 3/4 capillary leak syndrome was observed in 2 of the initial 7 patients but not after initiation of a dexamethasone prephase in the subsequent 14 patients. Of 17 evaluable patients, 24% achieved CR, 6% had partial response, and 47% had hematologic improvement for an overall activity rate of 70%. Further clinical trials with moxetumomab administered at higher doses or increased frequency in pediatric and adult ALL are currently underway.

CD52-directed therapy

For patients with T-ALL, the development of T cell-directed monoclonal antibody therapies are lagging compared with B-ALL. Alemtuzumab is a humanized monoclonal antibody against CD52. CD52 is expressed in 36% to 66% of leukemia cases, including B- and T-ALL and acute myeloid leukemia.58  Alemtuzumab has been investigated in small trials, but its development has been slow because of its modest activity and significant side effects. In 1 series, 3 children with relapsed T-ALL received alemtuzumab; none responded.59  Additional rare CRs with CD52-positive pre-B ALL have been reported with single agent alemtuzumab.60  Of note, CD52 is also expressed on normal and malignant B cells, although the experience using alemtuzumab in B-ALL has also been somewhat disappointing.61 

Conclusions

Developments of therapeutics with monoclonal antibodies in adult ALL are highly promising. Rituximab has been shown to improve survival when combined with conventional chemotherapy. Blinatumomab and inotuzumab have demonstrated marked activity even in patients with refractory ALL. The role of monoclonal antibodies and other novel targeted approaches in adult ALL continues to be defined. Most of these agents are currently being evaluated in the setting of ALL salvage, although the most active agents will likely need to be incorporated into the frontline regimens to optimize efficacy.

With several promising compounds moving into late stages of development, the leukemia community is facing a very hopeful development in ALL. Several questions are important. (1) Can multiple available monoclonal antibodies be incorporated into one regimen? (2) Should they be combined simultaneously or sequentially and what is the optimal sequence? (3) If regimens are designed that include multiple targeted therapies, how much chemotherapy is still needed to maintain or increase the current cure rate? (4) Will “chemotherapy” as we know it today be reserved for patients with relapsed-refractory ALL only (or patients who are prospectively predicted to benefit)? Although such suggestions still appear to be hypothetical, it is plausible that incorporating active monoclonal antibodies into frontline adult ALL therapy, in a concomitant or sequential fashion, may induce higher rates of MRD negativity and increase the cure rates to levels achieved in pediatric ALL and may reduce the need for intensive and prolonged chemotherapy schedules.

Authorship

Contribution: E.J., S.O., F.R., and H.K. wrote and approved the manuscript.

Conflict-of-interest disclosure: All authors received research grants from Amgen and Pfizer.

Correspondence: Elias Jabbour, Department of Leukemia, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030; e-mail: ejabbour@mdanderson.org.

References

References
1
Siegel
 
R
Naishadham
 
D
Jemal
 
A
Cancer statistics, 2013.
CA Cancer J Clin
2013
, vol. 
63
 
1
(pg. 
11
-
30
)
2
National Cancer Institute
 
SEER Stat Fact Sheet: Acute Lymphocytic Leukemia. Available at: http://seer.cancer.gov/statfacts/html/alyl.html. Accessed 2014
3
Pui
 
CH
Mullighan
 
CG
Evans
 
WE
Relling
 
MV
Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?
Blood
2012
, vol. 
120
 
6
(pg. 
1165
-
1174
)
4
Freireich
 
EJ
The history of leukemia therapy—a personal journey.
Clin Lymphoma Myeloma Leuk
2012
, vol. 
12
 
6
(pg. 
386
-
392
)
5
Pui
 
CH
Campana
 
D
Pei
 
D
, et al. 
Treating childhood leukemia without cranial irradiation.
N Engl J Med
2009
, vol. 
360
 
26
(pg. 
2730
-
2741
)
6
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
, vol. 
157
 
4
(pg. 
463
-
471
)
7
Fielding
 
AK
Rowe
 
JM
Buck
 
G
, et al. 
UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia.
Blood
2014
, vol. 
123
 
6
(pg. 
843
-
850
)
8
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
, vol. 
28
 
24
(pg. 
3880
-
3889
)
9
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
, vol. 
106
 
7
(pg. 
1569
-
1580
)
10
Stock
 
W
La
 
M
Sanford
 
B
, et al. 
Children’s Cancer Group; Cancer and Leukemia Group B studies
What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies.
Blood
2008
, vol. 
112
 
5
(pg. 
1646
-
1654
)
11
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
, vol. 
27
 
6
(pg. 
911
-
918
)
12
Rytting
 
M
Thomas
 
DA
O’Brien
 
S
, et al. 
Augmented Berlin-Frankfurt-Muenster based therapy for young adults with acute lymphoblastic leukemia (ALL).
Cancer
2014
, vol. 
120
 
23
(pg. 
3660
-
3668
)
13
Thomas
 
DA
Kantarjian
 
H
Smith
 
TL
, et al. 
Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy.
Cancer
1999
, vol. 
86
 
7
(pg. 
1216
-
1230
)
14
Tavernier
 
E
Boiron
 
JM
Huguet
 
F
, et al. 
GET-LALA Group; Swiss Group for Clinical Cancer Research SAKK; Australasian Leukaemia and Lymphoma Group
Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial.
Leukemia
2007
, vol. 
21
 
9
(pg. 
1907
-
1914
)
15
Gökbuget
 
N
Stanze
 
D
Beck
 
J
, et al. 
German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia
Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation.
Blood
2012
, vol. 
120
 
10
(pg. 
2032
-
2041
)
16
Piccaluga
 
PP
Arpinati
 
M
Candoni
 
A
, et al. 
Surface antigens analysis reveals significant expression of candidate targets for immunotherapy in adult acute lymphoid leukemia.
Leuk Lymphoma
2011
, vol. 
52
 
2
(pg. 
325
-
327
)
17
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 Lymphoma
2011
, vol. 
52
 
6
(pg. 
1098
-
1107
)
18
Rituxan (rituximab) Package Insert. San Francisco, CA; Genentech; 2012
19
Hoelzer
 
D
Gökbuget
 
N
Chemoimmunotherapy in acute lymphoblastic leukemia.
Blood Rev
2012
, vol. 
26
 
1
(pg. 
25
-
32
)
20
Rizzieri
 
DA
Johnson
 
JL
Byrd
 
JC
, et al. 
Alliance for Clinical Trials In Oncology (ACTION)
Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and Leukemia Group B study 10 002.
Br J Haematol
2014
, vol. 
165
 
1
(pg. 
102
-
111
)
21
Dworzak
 
MN
Schumich
 
A
Printz
 
D
, et al. 
CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy.
Blood
2008
, vol. 
112
 
10
(pg. 
3982
-
3988
)
22
Rubenstein
 
JL
Fridlyand
 
J
Abrey
 
L
, et al. 
Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma.
J Clin Oncol
2007
, vol. 
25
 
11
(pg. 
1350
-
1356
)
23
Clinicaltrials.gov
 
Intrathecal rituximab in lymphoid malignancies involving the central nervous system. Available at: www.clinicaltrials.gov. Accessed October 9, 2013
24
GlaxoSmithKline. Arzerra (ofatumumab) Package Insert. Research Triangle Park, NC: GlaxoSmithKline; 2011
25
Wierda
 
WG
Padmanabhan
 
S
Chan
 
GW
Gupta
 
IV
Lisby
 
S
Osterborg
 
A
Hx-CD20-406 Study Investigators
Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study.
Blood
2011
, vol. 
118
 
19
(pg. 
5126
-
5129
)
26
Jabbour
 
E
Kantarjian
 
H
Thomas
 
D
, et al. 
 
Phase II study of the hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with CD-20 positive acute lymphoblastic leukemia [abstract]. J Clin Oncol. 2014. Abstract 7065
27
Herter
 
S
Herting
 
F
Mundigl
 
O
, et al. 
Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models.
Mol Cancer Ther
2013
, vol. 
12
 
10
(pg. 
2031
-
2042
)
28
Goede
 
V
Fischer
 
K
Busch
 
R
, et al. 
Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.
N Engl J Med
2014
, vol. 
370
 
12
(pg. 
1101
-
1110
)
29
Scheuermann
 
RH
Racila
 
E
CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy.
Leuk Lymphoma
1995
, vol. 
18
 
5-6
(pg. 
385
-
397
)
30
Widdison
 
WC
Wilhelm
 
SD
Cavanagh
 
EE
, et al. 
Semisynthetic maytansine analogues for the targeted treatment of cancer.
J Med Chem
2006
, vol. 
49
 
14
(pg. 
4392
-
4408
)
31
Carol
 
H
Szymanska
 
B
Evans
 
K
, et al. 
The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse postinduction therapy in preclinical models of pediatric acute lymphoblastic leukemia.
Clin Cancer Res
2013
, vol. 
19
 
7
(pg. 
1795
-
1805
)
32
Younes
 
A
Kim
 
S
Romaguera
 
J
, et al. 
Phase I multidose-escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma.
J Clin Oncol
2012
, vol. 
30
 
22
(pg. 
2776
-
2782
)
33
Clinicaltrials.gov
 
SAR3419 in acute lymphoblastic leukemia. Available at: www.clinicaltrials.gov (NCT01440179). Accessed February 18, 2013
34
Borate
 
U
Fathi
 
AT
Shah
 
BD
, et al. 
A first-in-human phase 1 study of the antibody-drug conjugate SGN-CD19A in relapsed or refractory B-lineage acute leukemia and highly aggressive lymphoma [abstract].
Blood
 
2013;122(21). Abstract 1437
35
Nagorsen
 
D
Kufer
 
P
Baeuerle
 
PA
Bargou
 
R
Blinatumomab: a historical perspective.
Pharmacol Ther
2012
, vol. 
136
 
3
(pg. 
334
-
342
)
36
Topp
 
MS
Kufer
 
P
Gökbuget
 
N
, et al. 
Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival.
J Clin Oncol
2011
, vol. 
29
 
18
(pg. 
2493
-
2498
)
37
Topp
 
MS
Gökbuget
 
N
Zugmaier
 
G
, et al. 
Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL.
Blood
2012
, vol. 
120
 
26
(pg. 
5185
-
5187
)
38
Topp
 
MS
Gökbuget
 
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
, vol. 
32
 
36
(pg. 
4134
-
4140
)
39
Topp
 
MS
Goekbuget
 
N
Stein
 
AS
, et al. 
Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia.
Lancet Oncol
2015
, vol. 
16
 
1
(pg. 
57
-
66
)
40
Klinger
 
M
Brandl
 
C
Zugmaier
 
G
, et al. 
Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab.
Blood
2012
, vol. 
119
 
26
(pg. 
6226
-
6233
)
41
Carnahan
 
J
Wang
 
P
Kendall
 
R
, et al. 
Epratuzumab, a humanized monoclonal antibody targeting CD22: characterization of in vitro properties.
Clin Cancer Res
2003
, vol. 
9
 
10 Pt 2
(pg. 
3982S
-
3990S
)
42
Carnahan
 
J
Stein
 
R
Qu
 
Z
, et al. 
Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab.
Mol Immunol
2007
, vol. 
44
 
6
(pg. 
1331
-
1341
)
43
Raetz
 
EA
Cairo
 
MS
Borowitz
 
MJ
, et al. 
Children’s Oncology Group Pilot Study
Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Group Pilot Study.
J Clin Oncol
2008
, vol. 
26
 
22
(pg. 
3756
-
3762
)
44
Advani
 
A
McDonough
 
S
Coutre
 
S
, et al. 
Southwest Oncology Group Study S0910: a phase 2 trial of clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukemia.
Br J Haematol
2014
, vol. 
165
 
4
(pg. 
504
-
509
)
45
Sharkey
 
RM
Govindan
 
SV
Cardillo
 
TM
Goldenberg
 
DM
Epratuzumab-SN-38: a new antibody-drug conjugate for the therapy of hematologic malignancies.
Mol Cancer Ther
2012
, vol. 
11
 
1
(pg. 
224
-
234
)
46
Thomas
 
X
Inotuzumab ozogamicin in the treatment of B-cell acute lymphoblastic leukemia.
Expert Opin Investig Drugs
2012
, vol. 
21
 
6
(pg. 
871
-
878
)
47
Advani
 
A
Coiffier
 
B
Czuczman
 
MS
, et al. 
Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study.
J Clin Oncol
2010
, vol. 
28
 
12
(pg. 
2085
-
2093
)
48
Kantarjian
 
H
Thomas
 
D
Jorgensen
 
J
, et al. 
Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study.
Lancet Oncol
2012
, vol. 
13
 
4
(pg. 
403
-
411
)
49
Kebriaei
 
P
Wilhelm
 
K
Ravandi
 
F
, et al. 
Feasibility of allografting in patients with advanced acute lymphoblastic leukemia after salvage therapy with inotuzumab ozogamicin.
Clin Lymphoma Myeloma Leuk
2013
, vol. 
13
 
3
(pg. 
296
-
301
)
50
Kantarjian
 
H
Thomas
 
D
Jorgensen
 
J
, et al. 
Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia.
Cancer
2013
, vol. 
119
 
15
(pg. 
2728
-
2736
)
51
Deangelo
 
DJ
Stock
 
W
Shustov
 
AR
, et al. 
 
Weekly inotuzumab ozogamicin (InO) in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) [abstract]. Blood. 2013;122(21). Abstract 3906
52
Jabbour
 
E
O’Brien
 
S
Nitin
 
J
, et al. 
Inotuzumab ozogamicin (IO) in combination with low-intensity chemotherapy as front-line therapy for older patients and as salvage therapy for adult with relapse/refractory acute lymphoblastic leukemia [abstract].
J Clin Oncol
 
2014. Abstract 7019
53
Kreitman
 
RJ
Pastan
 
I
Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox.
Clin Cancer Res
2011
, vol. 
17
 
20
(pg. 
6398
-
6405
)
54
Kreitman
 
RJ
Stetler-Stevenson
 
M
Margulies
 
I
, et al. 
Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia.
J Clin Oncol
2009
, vol. 
27
 
18
(pg. 
2983
-
2990
)
55
Wayne
 
AS
Kreitman
 
RJ
Findley
 
HW
, et al. 
Anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-positive hematologic malignancies of childhood: preclinical studies and phase I clinical trial.
Clin Cancer Res
2010
, vol. 
16
 
6
(pg. 
1894
-
1903
)
56
Salvatore
 
G
Beers
 
R
Margulies
 
I
Kreitman
 
RJ
Pastan
 
I
Improved cytotoxic activity toward cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display.
Clin Cancer Res
2002
, vol. 
8
 
4
(pg. 
995
-
1002
)
57
Wayne
 
AS
Bhojwani
 
D
Silverman
 
LB
, et al. 
A novel anti-Cd22 immunotoxin, moxetumomab pasudotox: Phase I study in pediatric acute lymphoblastic leukemia (ALL) [abstract].
Blood
 
2011;118(21). Abstract 4977
58
Hu
 
Y
Turner
 
MJ
Shields
 
J
, et al. 
Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model.
Immunology
2009
, vol. 
128
 
2
(pg. 
260
-
270
)
59
Angiolillo
 
AL
Yu
 
AL
Reaman
 
G
Ingle
 
AM
Secola
 
R
Adamson
 
PC
A phase II study of Campath-1H in children with relapsed or refractory acute lymphoblastic leukemia: a Children’s Oncology Group report.
Pediatr Blood Cancer
2009
, vol. 
53
 
6
(pg. 
978
-
983
)
60
Laporte
 
JP
Isnard
 
F
Garderet
 
L
Fouillard
 
L
Gorin
 
NC
Remission of adult acute lymphocytic leukaemia with alemtuzumab.
Leukemia
2004
, vol. 
18
 
9
(pg. 
1557
-
1558
)
61
Tibes
 
R
Keating
 
MJ
Ferrajoli
 
A
, et al. 
Activity of alemtuzumab in patients with CD52-positive acute leukemia.
Cancer
2006
, vol. 
106
 
12
(pg. 
2645
-
2651
)