Monoclonal Antibodies in Pre-B ALL
Leukemia Insights - Spring 2012
The targeting of CD20 in ALL with combinations of rituximab and chemotherapy has improved survival in Burkitt leukemia and in CD20+ ALL. In the same light, several conjugated and unconjugated monoclonal antibodies targeting CD22 and CD19 are under study as almost all ALL leukemic cells also express these markers. Currently, four of these antibodies are of interest.
Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody bound to calicheamicin. Calicheamicin is a natural product of micromonospora echinospora and is significantly more toxic than chemotherapy1,2. Calicheamicin causes cell apoptosis by binding to the minor DNA groove and causing double-strand breaks. Inotuzumab delivers the conjugated calicheamicin by binding to CD22 with subnanomolar affinity where it is then internalized by the cell. Phase I-II studies have shown encouraging activity in lymphomas3,4 with durable response rates ranging from 60 to 80 percent. Phase II of the study proposed a dose schedule of 1.8 mg/m2 IV every 3-4 weeks and showed dose-limiting toxicities of myelosuppression and reversible liver function abnormalities.
Based on these results, a Phase II study of inotuzumab at a dose of 1.3 – 1.8 mg/m2 IV every 2-4 weeks was conducted in patients with refractory-relapsed ALL. A total of 49 patients received treatment, 75% were at or beyond Salvage 2. Thirty percent were either Ph+ or t(4;11) ALL. The results of the study showed a total of 28 patients achieving a response: 9 patients achieved CR, 14 patients achieved marrow CR without recovery of platelet counts, and 5 patients achieved marrow CR without recovery of neutrophil or platelet counts. Of these 28 patients, 16 patients achieved a complete cytogenetic response after showing chromosomal abnormalities at the start of therapy. Additionally, multiparameter flow cytometry for minimal residual disease showed 17 patients converted to MRD negative status. Treatment was well-tolerated with only 2 deaths due to non-drug-related complications within the first 4 weeks of therapy. Side effects included liver function abnormalities, 31% of which were severe but reversible.
The study results demonstrated a median survival rate of 4.5 months across all patients. The refractory nature of the study group is the likely cause of the shortened duration of response5. However, among the patients achieving marrow CR, the median survival rate was shown to be 6.7 months while the 9-month survival among the patients achieving CR was 78%. Furthermore, 22 of the 49 patients receiving treatment proceeded to allogeneic stem cell transplant.
This experience indicates that inotuzumab is a highly active single agent for the treatment of refractory-relapsed ALL. We are currently evaluating a weekly schedule of inotuzumab, which appears to be equally effective and less toxic than the single dose every 3-4 weeks. The study is open for accrual.
Blinatumomab is a bispecific, single chain antibody that invokes cell death in CD19- expressing ALL cells. Blinatumomab first engages the T-cell through an anti-CD3 arm. Once engaged, the T-cell is re-directed to bind to CD19-expressing ALL cells via its anti-CD19 arm. Within minutes after the T-cell and ALL cell are in contact, the T-cell becomes active and induces perforin-mediated death of the targeted ALL cell.
Topp et al. treated 21 ALL adult patients in first complete remission but with persistent minimal residual disease (MRD). Blinatumomab was given at a dose of 15 mcg/m2 daily by continuous infusion over 24 hours daily for 1 month with possible repeat of courses. Past experience indicated a very poor outcome of patients with ALL in first complete remission and persistent MRD unless they undergo allogeneic stem cell transplant promptly6. However, of the patients receiving treatment, 16 patients became MRD negative, 12 of which were molecularly refractory to prior chemotherapy. With a median follow-up of 15 months, the 1-year probability of relapse-free survival was 78% across all patients. For patients who did not undergo allogeneic stem cell transplant, the 1-year probability of relapse-free survival was 60%7.
More recently, blinatumomab was investigated in 18 patients with active refractory ALL. Early analysis reported marrow complete responses, including 9 CRs, in 12 patients treated. Blinatumomab is currently undergoing pivotal trials in refractory ALL with the aim of potential approval of this treatment as single-agent therapy. The study is open for accrual.
SAR3419 is an anti-CD19 antibody conjugated to maytansine. Only after it has been bound and taken up by the tumor cells is the active drug released from the immunoconjugate. Targeted therapy like SAR3419 has the potential for high efficacy and low toxicity.
Phase II studies in lymphoma showed response rates of 30 to 40 percent. This has led to a Phase II study of SAR3419 in adult ALL. SAR3419 is given intravenously weekly for 4 to 8 weeks (until CR), then every other week for another 12 doses. Patients are required to have adequate liver and kidney functions, and expression of CD19 on leukemia cells. The study is open for accrual.
Monoclonal antibodies, when linked to toxic moieties, form highly specific and potent anti-cancer agents called immunotoxins. A mixture of immunotoxins targeting CD19 and CD22 was recently proven to be effective in killing pre-B ALL cells in vitro8. Diphtheria toxin fused to IL-2 (DAB386IL2) or IL-3 (DT388IL3) is being tested for the treatment of patients with CLL and ALL, respectively. DT2219ARL is a genetically engineered fusion toxin protein consisting of the enzymatically active portion of diphtheria fused to the Fv fragments of the antibodies targeting the CD19 and CD22 cell surface receptors. In vitro, studies have shown specific and reproducible cytotoxic activity9.
We are participating in a Phase I multicenter study which is currently accruing. Patients will be treated with four every-other-day IV infusions.