This Month's Clinical Focus:  HEMATOLOGY

 Less Is More With Acute Myeloid Leukemia Drug
Study finds lower doses of cytarabine as effective, with fewer side effects, as standard dose.  A lower dose of the drug cytarabine works as well as the high doses that are typically used to treat acute myeloid leukemia, and with fewer side effects, a new Dutch study finds.

Cytarabine is used in the treatment of acute myeloid leukemia (AML), along with other chemotherapy drugs and stem cell transplantation. Cytarabine resembles a normal cell nutrient needed by cancer cells to grow. However, when these cells take up cytarabine, the drug actually interferes with their growth.

"The high-dose cytarabine schedules represent an unnecessary overdose causing excess toxicity with no apparent clinical benefit," said lead researcher Dr. Bob Lowenberg, a professor of hematology at Erasmus University Medical Center in Rotterdam. "The lower dose level is sufficient."

For the study, Lowenberg's team compared two different intravenous doses of cytarabine in patients with AML. One group of 431 patients was given a lower dose of the drug, while 429 were given a high dose, which is the current standard dose. Patients who had a complete response to the drug after the first two cycles were taken off the drug, and treatment continued with another type of chemotherapy or a stem cell implant.

Over five years of follow-up, the researchers found no difference between the two groups in terms of remission. Eighty percent of those who received the lower dose had a complete remission, as did 82 percent of those who were given the higher dose. There was also no significant difference in probability of relapse (34 percent of those given the lower dose and 35 percent of those who received the higher dose), or in overall survival (40 percent in the lower-dose group and 42 percent in the high-dose group).

Not only that, but patients receiving the high doses were more likely to suffer side effects than those given the lower doses, the researchers added. These included skin reactions and gastrointestinal and ocular toxic effects. Also, those given the high dose had longer hospital stays and delays in the recovery of white blood cells and platelets.

"The current standard of treatment with high-dose cytarabine, one of the major chemotherapeutic agents applied in the treatment of acute myeloid leukemia, represents an overdose," Lowenberg said. One-tenth of the standard dose produces equally effective treatment, but with less toxicity, shorter hospital stays and fewer transfusions, he added. "The lower-dose level also involves reduced costs," Lowenberg said. "These results set a new standard of care for the therapy of acute myeloid leukemia."

Dr. Mark H. Kirschbaum, an associate member for malignant hematology at the Nevada Cancer Institute in Las Vegas, said that "this is a very important study that will likely impact upon the treatment of patients with acute myeloid leukemia, particularly the older patient population, who clinically have always seemed to suffer from significant toxicity with higher-dose regimens. Hopefully progress in the molecular therapeutics of leukemia will allow us to more safely treat patients, particularly the older patients who make up the large majority of new AML patients, in a less toxic manner," he said.

Children with the rare condition hemoglobin H Constant Spring (HCS) -- named for the Jamaican town where it was first identified -- experience more severe anemia and require more transfusions than their counterparts with the more common hemoglobin H disease (HbH), a longitudinal study found.

Among patients with HCS, three-quarters had undergone at least one transfusion by age 10 years, as did 80% by age 20, according to Ashutosh Lal, MD, and colleagues from Children's Hospital and Research Center in Oakland, Calif.

The median age at first transfusion, which was usually required because of an acute drop in hemoglobin level during a febrile illness, was 5.9 years, Lal and colleagues reported in the Feb. 24 New England Journal of Medicine.

Patients with HCS have a mutation in the a2-globin gene adding 31 amino acids to the a globin chain, resulting in hemolysis and instability of hemoglobin. This mutation is largely found in persons with Southeast Asian ancestry.

In contrast, the more common, milder form of HbH is associated with deletion of two a-globin genes, which causes microcytic anemia, and has been found in both Asian and Mediterranean countries.

Because these disorders, which are types of a-thalassemia, have been on the rise in the U.S., Lal's group conducted a natural history study of 86 cases they had identified to ascertain whether the conditions should be included in newborn screening programs, as is already done in California.

A total of 70% of the patients had HbH, 27% had HCS, and the remaining 3% were other nondeletional forms of hemoglobin H disease. More than half of cases were detected through newborn screening.

The HbH patients were heterogeneous in ancestry, with origins from numerous Asian countries. This group also included some Hispanics and African Americans. The HCS patients were predominantly of Laotian and Chinese ancestry.

Among patients with HCS, first transfusions were needed when hemoglobin levels ranged from 2 to 7.4 g/dL, and the probability of undergoing at least one transfusion was 13% by the age of 1 year and 39% by the age of 5 years.

The finding that patients as young as 1 year needed transfusions "shows that life-threatening anemia may develop in infants before the diagnosis can be made through conventional means in the absence of newborn screening," they wrote.

Because most hemoglobin decreases that led to transfusions occurred during episodes of viral illness, preventive measures such as annual influenza immunizations should be provided, they advised.

The researchers concluded that their data weigh in favor of the inclusion of hemoglobin H syndromes in newborn screening programs. In an accompanying comment, Edward J. Benz Jr., MD, of Dana-Farber Cancer Institute in Boston, also argued in favor of screening for these disorders.

"We suggest that HCS be recognized as a thalassemia syndrome that is distinct from HbH so that the appropriate treatment approach can be devised for each group," they recommended.

"These results make a strong case for newborn screening for a-thalassemia, at least in states with a substantial increase in their Asian populations. The gene frequency for these disorders is high (up to 25% in some subgroups), and the screening tests are both inexpensive and virtually 100% accurate," Benz wrote.

SOURCE: article by Nancy Walsh, Staff Writer, MedPage Today

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