SAN DIEGO – The novel antibody blinatumomab induced high complete remission rates in adults with relapsed B-precursor acute lymphoblastic leukemia in early clinical trials, according to Dr. Max S. Topp.

In a phase II study with a dose-finding phase, 9 of 12 patients who received blinatumomab 5 mcg/m² per day for 1 week, followed by a 15-mcg dose on subsequent weeks, had either a complete remission (CR) or a CR with partial hematologic recovery (CRh), Dr. Topp of the University of Würzburg (Germany) said at the annual meeting of the American Society of Hematology.

"We have exceptionally high rates of hematological complete remissions in these patients, and it ought to be noted that every patient has achieved MRD [minimal residual disease] negativity," said Dr. Topp.

At a median follow-up of 9.7 months, the median overall survival had not been reached, he added.

Blinatumomab is a bispecific T-cell engager designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. It has shown good activity in a phase I clinical trial in patients with relapsed non-Hodgkin’s lymphoma, and in a study of patients with B-ALL who were positive for MRD (J. Clin. Oncol. 2011;29:2493-8).

The MT 103-206 trial was an open-label, multicenter phase II trial of blinatumomab in patients with relapsed/refractory B-precursor ALL, or Philadelphia chromosome–positive ALL (Ph+ALL) who were ineligible for tyrosine kinase inhibitors or who were in relapse following an allogeneic stem cell transplant.

The trial had a dose-finding run-in phase, with four patient cohorts. Dr. Topp focused on cohorts 2a and 3, in which patients received the selected dose schedule: an initial dose of 5 mcg/m² IV daily for the 1st week of cycle 1, followed by 15 mcg/m²per day for weeks 2-4 of every 4-week cycle, and every subsequent cycle. Patients had 2 weeks off between each cycle.

Patients who had a CR or CRh within the first two treatment cycles underwent consolidation with three additional cycles of blinatumonab and allogeneic stem cell transplant.

At the selected dose, the most common clinical adverse events were fever in 67%, headache in 33%, and tremor in 33%. Most of the events occurred during the first cycle, and no patients had to permanently discontinue therapy because of adverse events.

Among all cohorts (totaling 25 patients), there were 17 who had a CR or CRh: 5 of 7 patients who received a 15-mcg dose throughout treatment (cohort 1); 3 of 6 patients who received escalating doses of 5-, 15-, and 30-mcg doses (cohort 2b); and 9 of 12 patients in cohorts 2a and 3 combined. All patients with a CR or CRh were also MRD negative, defined as an MRD less than 104 measured by polymerase chain reaction evaluation of individual rearrangement of immunoglobulin or T-cell receptor genes by a central laboratory.

Dr. Topp explained that there were high response rates among all patient subgroups, including patients with Ph+ALL, and those with the t(4,11) translocation.

As of early November 2011, 6 of 17 patients with complete responses had relapses. One of four patients who had undergone allogeneic hematopoietic stem cell transplant had a medullary relapse; this patient was CD19 negative. A total of 5 of 13 patients had a relapse prior to transplant – 2 medullary relapses (1 CD19-negative and 1 positive) and 3 extramedullary relapses (1 CD19 negative and 2 positive).

One patient who had a medullary relapse but retained CD19 expression was retreated with blinatumomab and had a CRh of 7 months’ duration; the patient achieved a second, ongoing CRh after more blinatumomab.

The median duration of complete hematologic remission was 7.1 months (218 days) among 18 patients (12 responders) in cohorts 1, 2a, and 2b.

Asked in an interview whether an agent targeted against CD19 might work in combination with an anti-CD20 agent such as rituximab (Rituxan), Dr. Alan S. Wayne, a leukemia specialist and session comoderator who was not involved in the study, said that CD20 is not as attractive a target in ALL as it is in lymphoma or other hematologic malignancies.

"The question of CD20 in ALL is a little challenging, because the expression is less universal and even within individual cases across blasts," said Dr. Wayne, who is also head of the hematologic disease division of the pediatric oncology branch at the National Cancer Institute.

He noted, however, that there is evidence to suggest that pretreatment of patients with steroids may increase CD20 expression.

"This is an exciting new era for combining agents with a variety of different mechanisms of action, and also toxicity profiles. One could imagine, for example, [using] steroid to increase CD20 expression, rituximab, and then another CD19- or CD22-targeting agent," he said.

The MT 103-206 trial was supported by Micromet. Dr. Topp and coauthors Dr. Ralf Bargou and Dr. Nicola Goekbuget disclosed consulting for and/or receiving honoraria from the company. Three other coauthors are employees of the company. Dr. Wayne reported no relevant financial disclosures.

Blinatumomab Induces Complete Remissions in Acute Lymphoblastic Leukemia