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ALL: New Induction Regimen Appears Superior to Standard Therapy, with Quicker Time to Complete Response

Smith, Michael

doi: 10.1097/01.COT.0000292599.89095.fd

ORLANDO, FL—A novel induction regimen for adults with acute lymphocytic leukemia (ALL) appears to have an advantage over standard treatments on several measures, a seven-year study shows.

The regimen, called ALL-2, significantly shortened the time to complete remission to 32 from 55 days, a result that's important because the quicker a patient goes into remission, the higher is the likelihood of a cure, said Mark A. Weiss, MD, of Memorial Sloan-Kettering Cancer Center, who presented the results here at the ASCO Annual Meeting.

Also, in the subset of patients with the Philadelphia chromosome, a genetic predisposition that makes ALL harder to treat, the ALL-2 regimen made a statistically significant difference in both the incidence of complete remission and six-year survival, Dr. Weiss said.

“This is very different approach. We're very happy with it.”

The regimen also showed a trend toward improving the incidence of complete remission, but the result did not reach statistical significance, he said, adding that five-year survival was also not different between the novel and standard regimens.

ALL is relatively rare in adults—about 4,000 new cases a year in the United States and 1,500 deaths—but therapy has been relatively standard for many years, Dr. Weiss explained. “Almost everybody is going to treat this disease by starting with combination vincristine and prednisone and then adding some other drugs.”

The goal of induction therapy is to drive the disease into remission; the induction phase is then followed by consolidation with various drugs for up to two years.

Standard induction regimens, based on vincristine and prednisone, are capable of achieving complete remission in the majority of patients, Dr. Weiss said; adverse prognostic factors include a high white blood cell count, older age, the Philadelphia chromosome, or a time to remission of greater than five weeks.

“People who receive a remission early are more likely to be cured of their disease,” he said. “We wanted to develop faster regimens.”

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The ALL-2 regimen consisted of an induction phase of cytarabine (at 3 mg/m2/day for five days) combined with high-dose mitoxantrone (80 mg/m2 on Day 3) until remission was achieved. The induction phase was followed by consolidation with a vincristine/prednisone-based regimen.

ALL-2 was previously evaluated using historical controls—that data were reported in 1996 in the Journal of Clinical Oncology.

But in this study, the regimen was compared prospectively to standard induction therapy; 174 patients were randomized to ALL-2 (78 patients) or to a regimen (dubbed L-20) consisting of vincristine, prednisone, cyclophosphamide and doxorubicin (86 patients).

Accrual for the study started in 1997 and was completed in October 2004—a time course that Dr. Weiss said emphasizes the difficulty of randomized trials in a relatively rare disease. “We need to do a better job of getting people into clinical investigations,” he said.

In the experimental arm, the incidence of complete remission was 84%, compared with 71% in the L-20 arm. However, the result fell short of being significant, with a p-value of 0.06. On the other hand, the shortening of time to remission was highly significant, with a p-value of 0.001, Dr. Weiss reported.

In the difficult-to-treat subset of patients with the Philadelphia chromosome, the incidence of remission was 85%, compared with 47% in the L-20 arm; the result was significant at the p=0.04 confidence level.

As well, at six years, no patient with the chromosome was alive in the L-20 arm, compared with 26% in the experimental arm; the p-value was 0.04.

The result for these patients was “really uniquely better” than with standard therapy, Dr. Weiss said.

There were no significant differences in adverse events between the two arms and overall, Dr. Weiss concluded, the ALL-2 regimen “appears superior” to the L-20 regimen, although more follow-up is needed.

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‘Opens Door’

The study “opens the door to explore alternative induction regimens in randomized trials, and I congratulate Dr. Weiss—there have been only a few randomized trials recently in ALL,” commented Martin Tallman, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University and Chair of the Eastern Cooperative Oncology Group (ECOG) Leukemia Committee.

Dr. Tallman, who was the Discussant for several of the abstracts presented at the session, said that one message of the study is that conducting such randomized trials is difficult and time-consuming and needs multi-institution collaboration.

The study demonstrates that intensive induction is feasible, Dr. Tallman said, but it raises the question of whether the sequence of therapy is important; perhaps the message of Dr. Weiss' findings is that it's better to delay the vincristine/prednisone part of the therapy until after patients are in remission.

“Induction is less an issue than post-remission strategy, even in Ph-positive disease,” he said, noting that even with standard therapy, 80% to 90% of patients achieve remission.



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MRSA Infection Leads to Billions Per Year in Hospital Costs

Treating hospitalized patients who have methicillin-resistant Staphylococcus aureus in the United States costs an estimated $3.2 billion to $4.2 billion per year, according to a study presented at the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research.

“MRSA is acknowledged as a growing problem, but the associated medical costs are not well documented,” lead investigator Larry Liu, MD, PhD, Director of the US Outcomes Research Group at Pfizer Inc., noted in a news release.

Prolonged hospital stays and the use of intensive care units are the main contributors to the high medical costs of MRSA, he and his coauthor Erick Rojas, also of Pfizer, noted. Several studies have estimated medical costs associated with MRSA infections by infection type and individual institution, but the nationwide cost incurred by US hospitals was unknown.

© 2005 Lippincott Williams & Wilkins, Inc.
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