Optimal treatment for CML (Chronic Myeloid Leukemia)

What's the optimal treatment for CML (Chronic Myeloid Leukemia)?  In the New England Journal of Medicine (NEJM), there were a few interesting articles this week that caught my attention:

• Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia
• Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia

Both of these studies were comparing imatinib (Gleevec) to newer drugs (dasatinib or Sprycel and nilotinib or Tasigna). In both cases, the newer agent appeared to result in better clinical responses (see conclusions below). If this is now the case, where does imatinib fall into treatment regimens for CML?  Who's going to want to receive Gleevec for their CML?

Conclusions: Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML.

Conclusions: Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome–positive CML.

Arzerra (ofatumumab) for CLL approved by the FDA

FDA NEWS RELEASE

For Immediate Release: Oct. 26, 2009

Media Inquiries: Karen Riley, 301-796-4674, karen.riley@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA Approves New Treatment for Chronic Lymphocytic Leukemia

The U.S. Food and Drug Administration today approved Arzerra (ofatumumab) for patients with chronic lymphocytic leukemia (CLL), a slowly progressing cancer of the blood and bone marrow.

Arzerra is approved for patients with CLL whose cancer is no longer being controlled by other forms of chemotherapy.

CLL primarily affects people older than 50 and arises from a group of white blood cells known as B-cells that are part of the body’s immune system. Each year, about 16,000 people are diagnosed with CLL and about 4,400 people die from the disease.

Arzerra is a monoclonal antibody, a type of biotechnology product. Antibodies that occur in nature are produced by the immune system in response to invaders. Arzerra binds to a specific protein found on the surface of both normal and malignant B cells, making the cells more susceptible to immune system attack.

The product was approved under the FDA’s accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. Products may receive accelerated approval based on a surrogate endpoint, such as a reduction in the size of the tumor or decrease in the number of cancerous white cells or in an enlarged spleen or lymph nodes. These indirect measures for clinical outcomes are considered reasonably likely to predict that the drug will allow patients to live longer or with fewer side effects of a disease.

“The approval of Arzerra illustrates FDA's commitment to using the accelerated approval process to approve drugs for patients who have limited therapeutic options,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research.

The accelerated approval process requires further study of the drug. The manufacturer is currently conducting a clinical trial in CLL patients to confirm that the addition of Arzerra to standard chemotherapy delays the progression of the disease.

Arzerra's effectiveness was evaluated in 59 patients with CLL whose disease no longer responded to the available therapies.

The product’s safety was evaluated in 181 patients in two studies in patients with cancer. Common side effects included a decrease in normal white blood cells, pneumonia, fever, cough, diarrhea, lower red blood cell counts, fatigue, shortness of breath, rash, nausea, bronchitis and upper respiratory tract infections.

The most serious side effects of Arzerra are increased chance of infections, including progressive multifocal leukoencephalopathy (PML), a brain infection that is generally fatal. Patients at high risk for Hepatitis B should be screened before being treated with Arzerra. Patients with evidence of inactive hepatitis should be monitored for re-activation of the infection during and after completing treatment.

Arzerra is manufactured by London-based GlaxoSmithKline.

Arzerra (ofatumumab) appears promising for CLL

Arzerra (ofatumumab) appears promising for chronic lymphocytic leukemia (CLL). Ofatumumab (formerly known as HuMax-CD20) is a targeted therapy. It is actually a human monoclonal antibody that targets a distinct antibody binding site (the small loop epitope) of the CD20 molecule on the cell membrane of B cells. It is currently under development for the treatment of CLL and has also shown potential in treating follicular non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis. Is it available yet? No. The FDA is currently still reviewing this biologic agent. Here's a snippet from the June GSK press release:

GlaxoSmithKline and Genmab A/S today announced that the United States Food and Drug Administration (FDA) informed the companies that the agency has extended the action date for the ofatumumab BLA application by three months.

The FDA has been slow recently, don't you think? Better safe than sorry? Or, is the FDA being overly-cautious? We don't want to see another Raptiva incident again, do we? Raptiva was voluntarily withdrawn in April by Genentech because of an increased risk of progressive multifocal leukoencephalopathy (PML), a rare and usually fatal disease of the central nervous system. It's difficult to find such rare adverse effects until the drug gets used by the public, so I don't think anyone is faulting either the FDA or Genentech.

Well, let's see what happens with ofatumumab.