January 2015, Vol. 2, No. 1
Immunotherapy Attacks Minimum Residual Disease in ALL; Leads to High Rate of Complete Response
An antibody that recruits T cells to attack minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) who are in remission can prevent full relapse. No MRD was detected in 78% of patients treated with blinatumomab, a bispecific T-cell engager antibody construct, with nearly all complete responses occurring within the first cycle of treatment, said Nicola Gökbuget, MD, who presented the results of a phase 2 trial.
Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, and patients with high MRD have a high relapse risk after stem cell transplantation. Therefore, alternate treatment approaches to improve outcomes in patients with persistent or recurrent MRD are needed. In addition to evaluating blinatumomab in ALL, the study utilized a new, more sensitive method to detect MRD.
Blinatumomab was granted approval by the FDA on December 3, 2014, for the treatment of patients with Philadelphia chromosome–negative relapsed/refractory precursor B-cell ALL.
Blinatumomab directs cytotoxic T cells to CD19-positive cells, resulting in serial lysis. “CD19 is a highly specific B-cell marker that is expressed throughout B-cell development and in more than 90% of B-cell lineage cancers,” said Gökbuget, hematologic oncologist at Goethe University Hospital in Frankfurt, Germany. In a previously published small pilot trial of 20 patients, blinatumomab produced an 80% MRD response.
The study she presented here focused on a quantitative polymerase chain reaction–based method of individual gene rearrangement to measure MRD.
The open-label confirmatory phase 2 study enrolled 116 patients with MRD-positive B-cell precursor ALL, defined as a level ?10-3 in an assay with a minimum
sensitivity of 10-4, which is close to full relapse, said Gökbuget. Some 112 of the patients were evaluable for complete MRD response, the primary end point. Blinatumomab was given by continuous IV infusion, 15 µg/m2/day for 4 weeks followed by 2 weeks free of treatment (1 cycle) up to a maximum of 4 cycles. Hematopoietic stem cell transplantation was offered to eligible patients at any time after the first cycle.
Seventy-eight percent of patients who received at least 1 dose of blinatumomab had a complete MRD response; 98% of the complete responses occurred within the first cycle. Among 103 patients who received at least 1 dose of blinatumomab who were in complete remission at the start of treatment and had an MRD ?10-3 at screening, a complete MRD response after cycle 1 was achieved in 80%.
The vast majority of adverse events were grade <2. Two types of adverse events were recorded – those related to cytokine release (ie, fever, chills, fatigue) and those related to neurologic events. “The most commonly occurring adverse events were flu-like symptoms associated with T-cell activation,” she said.
Pyrexia was the most frequently reported adverse event, which occurred in 90%. Other adverse events related to cytokine release were chills (28%) and fatigue (24%). The most common gastrointestinal adverse events were nausea (22%), vomiting (22%), and diarrhea (20%). Grade ?3 adverse events were rare and included neutropenia (16%), pyrexia (7%), and tremor (5%).
The most frequent neurologic adverse events were tremor (29%) and aphasia (13%). Most were grade 1 or 2 but are clinically relevant, said Gökbuget, because they can lead to treatment interruption.
Using the body’s own defenses to kill cancer may sound like the realm of science fiction. However, in the keynote lecture presented at the 2015 Gastrointestinal Cancers Symposium, T cells and antibodies were shown adept at recognizing and targeting antigens created by tumor mutations as they evolve within patients. “The [ Read More ]
Two PD-1 inhibitors – the investigational drug nivolumab and the recently approved pembrolizumab – produced dramatic responses in patients with Hodgkin lymphoma in phase 1 clinical trials. Complete or partial responses were reported by up to 87% of patients who had exhausted other treatment options, providing solid evidence that targeting [ Read More ]