The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments.
This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation.
Progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.
Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population.
The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).
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For the last couple years, the UC San Diego Moores Cancer Center CLL program under the leadership of Dr. Thomas Kipps has been at the forefront of leading clinical trials for the use of ibrutinib (Imbruvica) and obinutuzumab (Gazyva) for patients with CLL. We are happy to announce that both iburtinub and obinutuzumab have been approved for treatment. Both drugs are considered “breakthrough therapies” under a program established by Congress last year. The new Breakthrough Therapy Designation indicates that the medicines may offer substantial improvement over standard treatments for patients with serious or life-threatening diseases. Both drugs demonstrate a shift for treatments away from chemotherapy.
Gazyva is an antibody that binds to CD20 a protein found on the surface of B cells and causes the cells, which are cancerous to die. It is the the first breakthrough monoclonal antibody drug to win FDA approval and will be used to treat patients with CLL who have not been previously treated. It will be used in combination with chlorambucil to attack cancerous cells. Patients who participated in the trial demonstrated a significant improvement in progression-free survival with an average of 23 months. Gazyva is being approved with a boxed warning regarding Hepatitis B virus reactivation and a rare disorder that damages the material that covers and protects nerves in the white matter of the brain (progressive multifocal leukoencephalopathy). These are known risks with other monoclonal antibodies in this class and rare cases were identified in participants on other trials of Gazyva. Patients should be advised of these risks and assessed for Hepatitis B virus and reactivation risk.
Imbruvica was approved for breakthrough treatment for relapses of mantle cell lymphoma and has also recently been applied for approval to treat CLL. It is an oral treatment and its approval was based the response rates of 111 patients. 65 percent of patients who received Imbruvica had a complete or partial response. Pharmacyclics officials said the label contained no black box warnings and no contraindications. Safety data during the drug’s pivotal trial showed the most common Grade 3 or 4 nonhematological adverse reactions (≥ 5 percent) included pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue and skin infection