June 15, 2011 (London, United Kingdom) — Blinatumomab, an investigational drug from a novel class known as BiTE antibodies, resulted in complete remission (CR) or complete remission with only partial hematologic recovery (CR+) in 9 of 12 patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL) in a small study.
Max Topp, MD, from the University Hospital of Wuerzburg, Germany, presented the interim results in a poster here at the 16th Congress of the European Hematology Association (EHA).
Blinatumomab appears to represent a new treatment option for patients with treatment-refractory ALL, he noted. "This is the first clinical evidence that this technology might provide the fifth pillar of cancer therapy. We are testing it in the most aggressive B-cell malignancy we know," he told Medscape Medical News in an interview.
The primary end point of the single-group, multicenter, exploratory phase 2 trial was the rate of CR or CR+. Secondary end points were toxicity and duration of response.
"Based on the results from the first 12 patients, there is reasonable hope that this will change the way we think about this disease," said Dr. Topp.
A previous phase 2 trial with blinatumomab, presented at the 2010 American Society of Hematology annual meeting, reported results from ALL patients who showed minimal residual disease (MRD) or leukemic cells in the bone marrow, despite having received chemotherapy. Results of this previous study showed that 80% (16 of 20) achieved MRD-negativity, all within the first treatment cycle. Disease-free survival was 60% after a follow-up of up to 27.5 months.
Dismal Prognosis for Relapsed/Refractory ALL
Blinatumomab is the first of a new class of agents designed to direct cytotoxic T-cells to CD19-expressing cancer cells. CD19 is a protein expressed on the surface of B-cell-derived ALLs and non-Hodgkin's lymphomas.
According to Dr. Topp, patients with refractory ALL have a dismal prognosis. Complete remission rates in this subset range from 17% to 45% with intensive chemotherapy, and treatment-related mortality rates range from 12% to 23%. "Even with the best chemotherapy currently available for these patients, such as FLAG/IDA [fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin], only 30% of patients will go into remission. Remission is then usually only of short duration, with a median of around 6 months," he explained.
In the current study, patients had difficult-to-treat B-precursor ALL, and all had relapsed after induction and consolidation therapy once or twice, or had refractory disease. The majority of patients had undergone allogeneic stem cell transplantation in addition to other chemotherapy.
After receiving blinatumomab, 9 of 12 patients reached the primary end point of CR or CR+; all 9 also reached the secondary end point of becoming MRD-negative or obtained molecular remission. Both CR and MRD were reached within the first cycle in responders, so it is "a precise and quick therapy," said Dr. Topp.
"This is unusual in this particular patient group," he remarked.
"This means there was a reduction in tumor burden of greater than 5 logs. This is very significant because the CR rate means a reduction of 1 log, but molecular remission equates to a reduction of 5 logs of tumor burden," he added.
The duration of response remains unknown in this particular trial, and will be reported at a later date, Dr. Topp noted. However, he cited a study he was involved with that was published online May 16 in the Journal of Clinical Oncology, which investigated the effect of blinatumomab on MRD and duration of response. "We found patients who are still MRD-negative after 2.5 years. Extrapolating from those data to this trial, there may be patients who experience a very similar clinical course," said Dr. Topp.
Various Dose Regimens
In the current study, there are 4 cohorts; interim data were presented for 2 of these. Patients in the first cohort received blinatumomab 15 mg as continuous infusion for 28 days in cycles 1, 2, 3, and 4. Five of 7 patients responded with CR or CR+.
In the second cohort, in the first week of cycle 1, patients received a lead-in phase of blinatumomab 5 μg/m2 per 24 hours; this was escalated to 15 μg/m2 per 24 hours for the remainder of cycle 1, and for cycles 2, 3, and 4.
"Remarkably, with this gradual dose escalation, there were no adverse events, yet we found the same CR rate as the first cohort. This is really very important," Dr. Topp emphasized.
The researchers' next step is to explore whether, in the third week, the dosage can be increased to 30 μg/m2 per 24 hours (the third cohort). Decisions about dosing will be made after completion of the other cohorts.
There were severe adverse events in the first cohort of patients. Most importantly, all events were completely reversible. One patient in the first cohort experienced cytokine release syndrome, and there were 2 patients with central nervous system events, which resolved after treatment was interrupted. In the second cohort, in which the initial dose was 5 μg/m2 per 24 hours, no severe adverse events related to the drug were reported.
Dr. Topp conceded that these results need to be confirmed in larger trials, and that the drug would need to be integrated into current treatment protocols, which could take many years of trials.
However, he foresees that this novel drug will fit in with established therapy. There are 4 established pillars of treatment for ALL: chemotherapy, radiotherapy, immunotherapy (e.g. rituximab), and small molecule tyrosine kinase inhibitors. Blinatumomab could represent a fifth pillar, he suggested.
Dr. Topp speculated that the mode of action of blinatumomab might potentially be useful in other cancers. "Beyond ALL, CD19 is expressed by all B-cell malignancies; we might also find other antigens that are as suitable, so this type of platform technology can be potentially used for solid tumors," he said.
Approached for comment, Bob Löwenberg, MD, winner of this year's EHA Jean Bernard Lifetime Achievement Award and professor of hematology at the Erasmus University in Rotterdam, the Netherlands, said the hematologic community will follow the clinical development of the antibody for therapeutic use with the greatest level of interest.
Early results in a notably unfavorable-risk population of patients with B-precursor ALL who had failed standard treatment show the promise of this antibody. Although the number of patients enrolled in this study is small, a few interesting responses were noted, suggestive of the highly potent activity of this agent. The bispecific antibody is of particular importance because it exploits a novel mode of action that combines pre-B-cell targeting with cytotoxic T-cell involvement," he told Medscape Medical News.
The study is being conducted by the German Multicenter Study Group for Adult Lymphoblastic Leukemia. Dr. Topp reports being a consultant for Micromet and Cellmedica, and receiving funds from Micromet AG to support his attendance at the EHA. Dr. Löwenberg has disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA): Abstract 844. Presented June 11, 2011.
Max Topp, MD, from the University Hospital of Wuerzburg, Germany, presented the interim results in a poster here at the 16th Congress of the European Hematology Association (EHA).
Blinatumomab appears to represent a new treatment option for patients with treatment-refractory ALL, he noted. "This is the first clinical evidence that this technology might provide the fifth pillar of cancer therapy. We are testing it in the most aggressive B-cell malignancy we know," he told Medscape Medical News in an interview.
The primary end point of the single-group, multicenter, exploratory phase 2 trial was the rate of CR or CR+. Secondary end points were toxicity and duration of response.
"Based on the results from the first 12 patients, there is reasonable hope that this will change the way we think about this disease," said Dr. Topp.
A previous phase 2 trial with blinatumomab, presented at the 2010 American Society of Hematology annual meeting, reported results from ALL patients who showed minimal residual disease (MRD) or leukemic cells in the bone marrow, despite having received chemotherapy. Results of this previous study showed that 80% (16 of 20) achieved MRD-negativity, all within the first treatment cycle. Disease-free survival was 60% after a follow-up of up to 27.5 months.
Dismal Prognosis for Relapsed/Refractory ALL
Blinatumomab is the first of a new class of agents designed to direct cytotoxic T-cells to CD19-expressing cancer cells. CD19 is a protein expressed on the surface of B-cell-derived ALLs and non-Hodgkin's lymphomas.
According to Dr. Topp, patients with refractory ALL have a dismal prognosis. Complete remission rates in this subset range from 17% to 45% with intensive chemotherapy, and treatment-related mortality rates range from 12% to 23%. "Even with the best chemotherapy currently available for these patients, such as FLAG/IDA [fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin], only 30% of patients will go into remission. Remission is then usually only of short duration, with a median of around 6 months," he explained.
In the current study, patients had difficult-to-treat B-precursor ALL, and all had relapsed after induction and consolidation therapy once or twice, or had refractory disease. The majority of patients had undergone allogeneic stem cell transplantation in addition to other chemotherapy.
After receiving blinatumomab, 9 of 12 patients reached the primary end point of CR or CR+; all 9 also reached the secondary end point of becoming MRD-negative or obtained molecular remission. Both CR and MRD were reached within the first cycle in responders, so it is "a precise and quick therapy," said Dr. Topp.
"This is unusual in this particular patient group," he remarked.
"This means there was a reduction in tumor burden of greater than 5 logs. This is very significant because the CR rate means a reduction of 1 log, but molecular remission equates to a reduction of 5 logs of tumor burden," he added.
The duration of response remains unknown in this particular trial, and will be reported at a later date, Dr. Topp noted. However, he cited a study he was involved with that was published online May 16 in the Journal of Clinical Oncology, which investigated the effect of blinatumomab on MRD and duration of response. "We found patients who are still MRD-negative after 2.5 years. Extrapolating from those data to this trial, there may be patients who experience a very similar clinical course," said Dr. Topp.
Various Dose Regimens
In the current study, there are 4 cohorts; interim data were presented for 2 of these. Patients in the first cohort received blinatumomab 15 mg as continuous infusion for 28 days in cycles 1, 2, 3, and 4. Five of 7 patients responded with CR or CR+.
In the second cohort, in the first week of cycle 1, patients received a lead-in phase of blinatumomab 5 μg/m2 per 24 hours; this was escalated to 15 μg/m2 per 24 hours for the remainder of cycle 1, and for cycles 2, 3, and 4.
"Remarkably, with this gradual dose escalation, there were no adverse events, yet we found the same CR rate as the first cohort. This is really very important," Dr. Topp emphasized.
The researchers' next step is to explore whether, in the third week, the dosage can be increased to 30 μg/m2 per 24 hours (the third cohort). Decisions about dosing will be made after completion of the other cohorts.
There were severe adverse events in the first cohort of patients. Most importantly, all events were completely reversible. One patient in the first cohort experienced cytokine release syndrome, and there were 2 patients with central nervous system events, which resolved after treatment was interrupted. In the second cohort, in which the initial dose was 5 μg/m2 per 24 hours, no severe adverse events related to the drug were reported.
Dr. Topp conceded that these results need to be confirmed in larger trials, and that the drug would need to be integrated into current treatment protocols, which could take many years of trials.
However, he foresees that this novel drug will fit in with established therapy. There are 4 established pillars of treatment for ALL: chemotherapy, radiotherapy, immunotherapy (e.g. rituximab), and small molecule tyrosine kinase inhibitors. Blinatumomab could represent a fifth pillar, he suggested.
Dr. Topp speculated that the mode of action of blinatumomab might potentially be useful in other cancers. "Beyond ALL, CD19 is expressed by all B-cell malignancies; we might also find other antigens that are as suitable, so this type of platform technology can be potentially used for solid tumors," he said.
Approached for comment, Bob Löwenberg, MD, winner of this year's EHA Jean Bernard Lifetime Achievement Award and professor of hematology at the Erasmus University in Rotterdam, the Netherlands, said the hematologic community will follow the clinical development of the antibody for therapeutic use with the greatest level of interest.
Early results in a notably unfavorable-risk population of patients with B-precursor ALL who had failed standard treatment show the promise of this antibody. Although the number of patients enrolled in this study is small, a few interesting responses were noted, suggestive of the highly potent activity of this agent. The bispecific antibody is of particular importance because it exploits a novel mode of action that combines pre-B-cell targeting with cytotoxic T-cell involvement," he told Medscape Medical News.
The study is being conducted by the German Multicenter Study Group for Adult Lymphoblastic Leukemia. Dr. Topp reports being a consultant for Micromet and Cellmedica, and receiving funds from Micromet AG to support his attendance at the EHA. Dr. Löwenberg has disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA): Abstract 844. Presented June 11, 2011.
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