ROR1, an oncogene recently discovered on chronic lymphocytic leukemia (CLL) B cells, is being studied by researchers as a potential target for CLL treatment. Dr. Brian Koffman met with Dr. Thomas Kipps, who is researching ROR1, at the 2014 American Society of Clinical Oncology (ASCO) meeting to discuss this oncogene and its potential use in treating CLL.
As more chronic lymphocytic leukemia CLL treatments are approved, with many more in development, are researchers closer to hitting a “home run” in treating the disease? Patient advocate Dr. Brian Koffman met with CLL expert Dr. Thomas Kipps at ASCO 2014 to explore emerging therapies and the goal for patients to achieve deep remission.
Published on the August 7th (2014) in the journal of Genome Biology:
Accurate allele frequencies are important for measuring subclonal heterogeneity and
clonal evolution. Deep-targeted sequencing data can contain PCR duplicates, inflating perceived read depth. Here we adapted the Illumina TruSeq Custom Amplicon kit to include single molecule tagging (SMT) and show that SMT-identified duplicates arise from PCR. We demonstrate that retention of PCR duplicate reads can imply clonal evolution when none exists, while their removal effectively controls the false positive rate. Additionally, PCR duplicates alter estimates of subclonal heterogeneity in tumor samples. Our method simplifies PCR duplicate identification and emphasizes their removal in studies of tumor heterogeneity and clonal evolution.
Lenalidomide has demonstrated clinical activity in patients with chronic lymphocytic leukemia (CLL), even though it is not cytotoxic for primary CLL cells in vitro. We examined the direct effect of lenalidomide on CLL-cell proliferation induced by CD154-expressing accessory cells in media containing interleukin (IL)-4 and IL-10. Treatment with lenalidomide significantly inhibited CLL-cell proliferation, an effect that was associated with the p53-independent upregulation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21). Silencing p21 with small interfering RNA (siRNA) impaired the capacity of lenalidomide to inhibit CLL-cell proliferation. Silencing cereblon (CRBN), a known molecular target of lenalidomide, impaired the capacity of lenalidomide to induce expression of p21, inhibit CD154-induced CLL-cell proliferation, or enhance the degradation of Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3).
We isolated CLL cells from the blood of patients before and after short-term treatment with low-dose lenalidomide (5 mg per day) and found the leukemia cells also were induced to express p21 in vivo. These results indicate that lenalidomide can directly inhibit proliferation of CLL cells in a CRBN/p21-dependent, but p53-independent, manner at concentrations achievable in vivo, potentially contributing to the capacity of this drug to inhibit disease-progression in patients with CLL.
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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ROR1 can interact with TCL1 and enhance leukemogenesis in Eμ-TCL1 transgenic mice.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen found on chronic lymphocytic leukemia (CLL) B cells, but not on normal adult tissues. We generated transgenic (Tg) mice with human ROR1 regulated by the murine Ig promoter/enhancer. In contrast to nontransgenic littermates, such animals had B-cell-restricted expression of ROR1 and could develop clonal expansions of ROR1(bright)CD5(+)B220(low) B cells resembling human CLL at ≥ 15 mo of age. Because immune-precipitation and mass spectrometry studies revealed that ROR1 could complex with T-cell leukemia 1 (TCL1) in CLL, we crossed these animals with Eµ-TCL1-Tg (TCL1) mice. Progeny with both transgenes (ROR1 × TCL1) developed CD5(+)B220(low) B-cell lymphocytosis and leukemia at a significantly younger median age than did littermates with either transgene alone. ROR1 × TCL1 leukemia B cells had higher levels of phospho-AKT than TCL1 leukemia cells and expressed high levels of human ROR1, which we also found complexed with TCL1.
Transcriptome analyses revealed that ROR1 × TCL1 leukemia cells had higher expression of subnetworks implicated in embryonic and tumor-cell proliferation, but lower expression of subnetworks involved in cell-cell adhesion or cell death than did TCL1 leukemia cells. ROR1 × TCL1 leukemia cells also had higher proportions of Ki-67-positive cells, lower proportions of cells undergoing spontaneous apoptosis, and produced more aggressive disease upon adoptive transfer than TCL1 leukemia cells. However, treatment with an anti-ROR1 mAb resulted in ROR1 down-modulation, reduced phospho-AKT, and impaired engraftment of ROR1 × TCL1 leukemia cells. Our data demonstrate that ROR1 accelerates development/progression of leukemia and may be targeted for therapy of patients with CLL.
We have our new newsletter is available!! New news and articles letting you know the latest news in regards to CLL and the Blood Cancer Research Fund. Special thanks to Carolina Bump for her tireless efforts to get this information together!
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