TORONTO, June 9 — A stem cell transplant from a compatible donor should be the preferred treatment for people with intermediate-risk acute myeloid leukemia (AML), according to a new meta-analysis of prospective studies.

• Explain to interested patients that stem cell transplants from a compatible donor are regarded as the treatment of choice for patients with poor-risk acute myeloid leukemia, but are not recommended for those in the good-risk category.
• Note that this meta-analysis found that the benefit of such a transplant extends to the majority of patients, who fall in the middle of those two risk groups.

In these patients, such an allogeneic transplant reduces the risk of relapse or death by 20%, compared with a nonallogeneic transplant, according to John Koreth, D.Phil., of the Dana Farber Cancer Institute in Boston, and colleagues.

Allogeneic transplants have been considered the best treatment for patients whose chromosome changes put them in the poor-risk category, Dr. Koreth and colleagues said in the June 10 issue of the Journal of the American Medical Association.

Other therapies are considered more appropriate for those in the good-risk category. But there has been no consensus on how to treat the majority of patients who have intermediate risk, they said.

To clarify the issue, the researchers undertook a systematic review and meta-analysis of prospective studies that stratified patients on the basis of chromosomal risk categories and evaluated the difference in outcomes between allogeneic and nonallogeneic transplants.

The usual treatment for AML involves an “induction” phase that uses chemotherapy to put the disease into a first remission. The next stage, “consolidation,” is intended to be curative, and with options that include more chemotherapy, transplant using a patient’s own stem cells, and allogeneic transplant.

“Allogeneic transplants have been shown to be very effective for many AML patients with aggressive disease,” Dr. Koreth said in a statement. But “it has never been comprehensively shown which patients stand to benefit significantly from the procedure.”

For those with poor- and good-risk disease, the study is “reassurance” that current treatment recommendations are correct, he said.

“Our finding that people with intermediate-risk AML benefit significantly from allogeneic transplant in first remission should establish it as the preferred treatment for this group,” he added.

All told, Dr. Koreth and colleagues found 24 trials, involving 6,007 patients, that met their criteria. Relapse-free survival was evaluated for 5,951 patients and overall survival for 5,606. In the studies, 3,638 patients were analyzed by risk category, including 547 good-risk, 2,499 intermediate-risk, and 592 poor-risk patients respectively.

Compared with nonallogeneic transplant, the researchers found, the hazard ratio of relapse or death with an allogeneic transplant for patients in first remission was 0.80 (95% CI 0.74 to 0.86).

But when the analysis was broken down by risk category and outcome, they found:

• Poor-risk patients had a hazard ratio for relapse-free survival of 0.69 ((95% CI 0.57 to 0.84) if they got an allogeneic transplant.
• Intermediate-risk patients had a similar significant benefit — a hazard ratio of 0.76; (95% CI 0.68 to 0.85).
• But for good-risk patients, the hazard ratio was 1.06, which was not significant.
• For overall survival, the benefit was significant in poor-risk and intermediate-risk patients — with hazard ratios of 0.73 and 0.83, respectively (95% CI 0.59 to 0.90 and 0.74 to 0.93).
• But again, there was no significant effect for good-risk patients, with a hazard ratio of 1.07 (95% CI 0.83 to 1.38).

One limitation of the study is that some pertinent trials have not yet been published, the researchers said.

As well, they noted, not all clinical data could be extracted from the studies, making it possible that the finding is not applicable to all patients. For instance, they said, age is likely a relevant factor, and since the median age in most studies was in the 30s, it remains unclear whether older patients benefited in the same way.

The authors did not report any external support for the study. Dr. Koreth did not report any financial disclosures.

Primary source: Journal of the American Medical Association

Source reference:

Koreth J, et al “Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials” JAMA 2009; 301(22): 2349-61.

In a study comparing two strains of mice, one susceptible to developing cancer and the other not, researchers found that a high-fat diet predisposed the cancer-susceptible strain to liver cancer, and that by switching to a low-fat diet early in the experiment, the same high-risk mice avoided the malignancy. The switched mice were lean rather than obese and had healthy livers at the end of the study.

The findings, from a joint University of Pennsylvania School of Medicine and Case Western Reserve University study, appear online this month in Human Molecular Genetics.

The investigators studied hepatocellular carcinoma (HCC), a type of liver cancer that is one of the leading causes of cancer death worldwide. Thirty percent of cases of this type of liver cancer are associated with diabetes, and related metabolic diseases, although a direct link between these and liver cell cancer has not been completely established. “The connection between obesity and cancer is not well understood at this point,” says senior co-author John Lambris, PhD, the Dr. Ralph and Sallie Weaver Professor of Research Medicine at Penn. The researchers hope the results will lead to the development of blood tests that can detect precancerous conditions related to diet.

The remaining seventy percent of HCC cases result from hepatitis B and C viral infections, exposure to the fungal toxin aflatoxin, chronic alcohol use, or genetic liver diseases.

The usual outcome of hepatocellular carcinoma is poor, because only 10 to 20 percent of these tumors can be surgically removed. If the cancer cannot be completely removed, the disease is usually deadly within 3 to 6 months. Hepatocellular carcinoma causes close to 700,000 deaths worldwide per year, mostly outside the US.

The researchers tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that one strain, named C57BL/6J, was susceptible to non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma on a high-fat, but not a low-fat diet. The other strain, called A/J, was not susceptible to disease on a high-fat diet. The mice were fed their respective diets for close to 500 days, weighed periodically, and then analyzed for the presence of disease.

RNA profiles of hepatocellular carcinoma versus tumor-free liver tissue at the end of the experiment showed that two signaling networks one centered on Myc and the other on NF-kappa B were involved. This result is similar to findings obtained from studies on the two major classes of hepatocellular carcinoma in humans.

At the end of the experiment, mice susceptible to cancer showed characteristics of NASH such as inflammation and fibrosis, and, in some cases, cirrhosis as well as hepatocellular carcinoma, in their livers. A switch from a high-fat to a low-fat diet reversed these outcomes in groups of C57BL/6J mice that were fed a high-fat diet early in the experiment. The switched C57BL/6J mice were lean rather than obese and had healthy livers at the end of the study. All mice kept on a high-fat diet for the duration of the experiment had liver tumors at the end of 500 days.

A similar change in diet may have important implications for preventing liver cancers in humans, suggest the researchers. “The reason these findings are so provocative is that it relates to diet and we now have a unique model we know will develop cancer,” says Lambris.

“By waiting for evidence of disease before terminating the study, instead of using an arbitrary endpoint as is done in most experimental studies, we were able to discover an important new experimental model for a common cancer in humans,” says senior co-author Joseph Nadeau, Professor and Chair of the Department of Genetics at Case Western Reserve University School of Medicine.

The work was funded by the National Center for Research Resources and the Charles B. Wang Foundation.

Co-authors, in addition to Lambris and Nadeau are Maciej M. Markiewski from Penn, Annie E. Hill-Baskin, David A. Buchner, Haifeng Shao, David DeSantis, Nathan A. Berger, and Colleen Croniger from Case Western, and Gene Hsiao, and Shankar Subramaniam from University of California, San Diego.

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System.

Penn’s School of Medicine is currently ranked #3 in the nation in U.S.News & World Report’s survey of top research-oriented medical schools; and, according to the National Institutes of Health, received over $366 million in NIH grants (excluding contracts) in the 2008 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s top ten “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation’s first hospital; and Penn Presbyterian Medical Center, named one of the nation’s “100 Top Hospitals” for cardiovascular care by Thomson Reuters. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

Source: University of Pennsylvania School of Medicine

In 2010, cancer will be the single leading cause of death worldwide, overtaking chronic illnesses such as heart disease and stroke. Already cancer causes more deaths than HIV/AIDS, tuberculosis and malaria combined. Almost three-quarters of new cases will occur in developing countries, with more than a million cases in sub-Saharan Africa by 2020, according to who.int/” rel=”nofollow”>World Health Organization projections.

Scot Remick, M.D., director of the Mary Babb Randolph Cancer Center at West Virginia University, is leading U.S. efforts to help prepare for the growing cancer burden in Third World nations. He heads the International Working Group of the National Cancer Institute’s AIDS Malignancy Consortium, which has been instrumental in training doctors and building clinical trials for AIDS-related diseases in Uganda and Kenya.

“Most people don’t realize that by 2010 cancer will be the single greatest cause of mortality worldwide,” said Remick after returning from the May-June meeting of the American Society of Clinical Oncology, where he chaired an education session on the topic. “Anywhere from 15 to 20 percent of cancers are due to transmissible causes, and healthcare professionals in the industrialized world are likely to underestimate the role of infectious agents even though they constitute a significant burden.”

Transmissible causes include viruses such as Epstein-Barr virus, human immunodeficiency virus (HIV), Hepatitis B and Hepatitis C viruses, and the human papillomavirus. Viruses may hit the developing world particularly hard, but rising rates of obesity and tobacco use are a factor, too.

“You’re beginning to see Western influences on lifestyle, and this is creating impact on the cancer rate,” Remick said.

Remick and an international team of researchers have just published results of the first clinical trial of its type in Africa a low-dose chemotherapy regimen for people with AIDS-related non-Hodgkin’s lymphoma. The trial showed dramatic results a 6 percent mortality rate, compared with an expected 20 percent to 66 percent rate in the Kenyan and Ugandan populations studied.

The research team chose a low-dose chemotherapy regimen because it’s vital that cancer therapies in sub-Saharan Africa be less myelotoxic or damaging to bone marrow than conventional treatment plans. Money, means and blood products may not exist in resource-challenged countries to counteract chemotherapy’s potentially destructive effects on bone marrow.

Remick, senior researcher on the study published in the current issue of the Journal of Clinical Oncology, said the clinical trial represents a dozen years of work. Partners in the project are Case Western Reserve University in Ohio, Ohio State University, the Uganda Cancer Institute and Kenyatta National Hospital as well as medical schools in Uganda and Kenya.

The AIDS Malignancy Consortium will be promoting measures such as vaccination and other strategies aimed at preventing cancer as well as screening programs to encourage early diagnosis. Development of more low-dose chemotherapy trials is also on the agenda.

“The hope is that, as things will evolve, our efforts will be less about awareness and advocacy and more about action,” Remick said.

Source: West Virginia University Health Sciences Center