Monoclonal antibodies in adult acute lymphoblastic leukemia

Abstract

Monoclonal antibodies taregeting surface markers in acute lumphocytic leukemia (CD19, CD20 and CD22) are showing promising results and are reviewed.

Keywords:

• Inotuzomab
• Blinatumomab
• Monoclonal antibodies

Introduction

Combination chemotherapy programs have increased the cure rate in adult acute lymphoblastic leukemia (ALL) from less than 20% up to 35–50%.1 The addition of asparaginase to chemotherapy regimens further improved the cure rates at the expense of significant toxicity, particularly in patients >45 years.2 Further intensification of regimens is unlikely to increase the cure rate and may increase toxicities. Novel anti-ALL agents or strategies are needed to improve adult ALL prognosis.

Targeted therapy in ALL is promising. In Philadelphia, chromosome-positive ALL, BCR–ABL tyrosine kinase inhibitors added to intensive chemotherapy have increased survival rates from less than 10% to 50%.3 Monoclonal antibodies against cell surface markers of ALL cells are showing promise.

Surface Antigens Expression on Lymphoblasts and Potential Targeted Monoclonal Antibodies

Several differentiation antigens expressed on the surface of lymphoblasts are targetable with existing monoclonal antibodies. Expression of CD20 is noted in approximately 25–50%, CD22 in more than 90%, and CD19 in nearly all cases.

Unconjugated monoclonal antibodies include CD20 monoclonal antibodies like rituximab, and the more potent antibodies ofatumomab and GA-101. Monoclonal antibodies conjugated to cytotoxic agents include inotuzumab ozogamicin (CD22 monoclonal antibody conjugated to calecheamicin), SAR3419 (CD19 monoclonal antibody conjugated to maytansin, a potent antimitotic cytotoxic drug), and others. Monoclonal antibodies have also been conjugated with toxins such as Pseudomonas and diphtheria toxins. Blinatumomab is a bispecific monoclonal antibody directing CD3 cytotoxic T cells to CD19 surface antigens on ALL cells.

Rituximab

Mature B-ALL and Burkitt leukemia exhibit strong CD20 expression. Hyper-CVAD chemotherapy was combined with rituximab, producing a complete response (CR) rate of 95%. Compared with hyper CVAD without rituximab (n = 44), the addition of rituximab resulted in a 4-year survival rate of 77% versus 50% (P = 0·03).4 The German study group also combined chemotherapy with rituximab (total of eight doses). Among 146 patients treated, the CR rate was 90%; the 3-year survival rate among patients younger than 55 years was 91%, and among patients 55 years or older, it was 84%. In the subset of patients with mature B-ALL (n = 84), the CR rate was 83%; the 3-year survival rate was 79% among younger patients and 39% among older patients.5 Similar results were reported by others. Thus, chemotherapy and rituximab is the new standard of care in mature B-ALL and Burkitt lymphoma.

Rituximab was added to hyper-CVAD chemotherapy in patients with CD20 positive pre-B ALL (non-Burkitt). The overall CR rate was 95%, and the 3-year rates of CR duration and survival were 60% and 50%, respectively, better than historical experience with chemotherapy alone.6 In a German study of chemotherapy plus rituximab among younger patients (age <60 years) with CD20 positive ALL, chemo-immunotherapy was associated with significantly higher rates of CR durations (70% versus 38%; p <0·01) and survival (75% versus 47%; P = 0·003). Among patients younger than 55 years, the addition of rituximab was associated with a 5-year remission duration rate of 80% versus 47% without rituximab, and with a 5-year survival rate of 71% versus 51% without rituximab.7

Blinatumomab (CD3+CD19+Bispecific Monoclonal Antibody)

Blinatumomab is a novel bispecific single chain antibody which engages T cells with its anti-CD3 arm and redirects them via its anti-CD19 other arm to CD19 expressing lymphoblasts. Topp et al. treated 21 adults with ALL in first CR and persistent minimal residual disease (MRD) with blinatumomab 15 mcg/m² by continuous infusion over 24 hours daily for 4 weeks. Sixteen of 21 patients became MRD-negative. With a median follow-up of 15 months, the 1-year probability of relapse-free survival was 78%.8 Blinatumomab was then investigated in active refractory/relapsed ALL; marrow CRs were noted in 12 of 18 patients treated.9

Inotuzumab (CD22 Monoclonal Antibody Conjugated to Calecheamicin)

Inotuzumab ozogamicin is a CD22 monoclonal antibody bound to calecheamicin, a toxic natural product of Micromonospora echinospora. In a phase II study of inotuzumab 1·3–1·8 mg/m² i.v. every 3–4 weeks in 49 patients with refractory/relapsed ALL, 65% were in salvage ⩾2. Overall, 9 (18%) achieved CR, 14 (29%) had marrow CR without recovery of platelet counts, and 5 (10%) had marrow CR without recovery of neutrophil or platelet counts.10 The overall response rate was 57%. Among 18 with chromosomal abnormalities at the start of therapy, who achieved CR, 16 (89%; 43% of all patients) achieved a complete cytogenetic response. Multiparameter flow cytometry for MRD showed reversal to MRD negative status in 17 of 27 patients (63%). The median survival of all patients was 4·5 months. Among the nine patients achieving CR, the estimated 9-month survival was 78%. Subsequent studies will evaluate inotuzumab in earlier salvage therapy, in combination with chemotherapy for frontline ALL therapy, for the treatment for MRD.10

Other Monoclonal Antibodies Conjugated to Cytotoxic Agents or to Immunotoxins

SAR3419 is a humanized IgG1 CD19 monoclonal antibody conjugated to maytansin, a highly potent tubulin inhibitor. A phase 2 study of SAR3419 given at a dose of 55–70 mg/m² i.v. weekly ×4, then every other week ×4 is ongoing in adult refractory-relapsed ALL. CD19 and CD22 monoclonal antibodies conjugated with auristatin, another cytotoxic spindle tubulin inhibitor, are available.

BL22 (CAT-3888) is an anti-CD22 immunotoxin composed of an Fv derived from a monoclonal antibody directed towards CD22 and fused to a 38-kDa fragment of Pseudomonas aeruginosa exotoxin A. BL22 was active in phase 1–2 human studies in hairy cell leukemia. Wayne et al. evaluated BL22, 10–40 mcg/kg every other day for three or six doses every 3–4 weeks, in childhood ALL. Among 23 patients treated, 16 (70%) showed reductions of leukemic blasts. A new higher affinity version of BL22 (named HA22; high-affinity BL22; CAT-8015; moxetumomab pasudotox) was evaluated in ALL. Among 19 evaluable patients with active childhood ALL treated with HA22 5–40 mcg/kg i.v. every other day ×6, four patients achieved complete responses, one had a partial response, and eight patients had hematological improvement.11

Conclusions

Several monoclonal antibodies are active in ALL. Future studies will establish their role in the salvage setting and in frontline therapy for high risk adult ALL. Older patients with de novo ALL have very poor tolerance to current frontline chemotherapy regimens. Low-intensity chemotherapy with monoclonal antibodies or combinations of monoclonal antibodies with minimal or no chemotherapy should be studied. Combinations of monoclonal antibody therapies with or without chemotherapy could be potentially curative in ALL.