Imatinib Boosts Survival of ALL Patients Undergoing Transplant

Roxanne Nelson

December 05, 2010

December 5, 2010 (Orlando, Florida) — Early use of imatinib (Gleevec; Novartis) during induction for Philadelphia + (Ph+) acute lymphoblastic leukemia (ALL) can significantly enhance transplantation outcomes, according to data reported here at the American Society of Hematology 52nd Annual Meeting.

Imatinib significantly enhanced complete response rates and increased the allogeneic hematopoietic stem cell transplant (alloHSCT) rate. The authors note that in turn, these effects translate into a highly significant event-free, relapse-free, and overall survival advantage.

Dr. Adele K. Fielding

Before the use of imatinib, only 28% of patients went on to receive alloHSCT as per protocol. However, that number has risen to 44% with imatinib.

Overall survival at 3 years for patients who received per protocol alloHSCT was 59% compared with 28% for those who were not transplanted. However, before imatinib, the 5-year overall survival rate was 40% for those who received transplants vs 19% for nontransplanted patients.

"These study results demonstrate for the first time that there is a long-term survival advantage of being treated with imatinib earlier in the treatment protocol," said lead author Adele K. Fielding, MBBS, PhD, senior lecturer, University College London, in the United Kingdom.

"Although there have been a number of studies outlining the value of imatinib in this disease, this is the largest such study," she said during a briefing to the press. "Because of the very large number of patients on the same study without imatinib, it allows us to make some very sensible conclusions."

It allows us to make some very sensible conclusions.

However, she also points out that the extent to which imatinib can improve outcomes in adult Ph+ ALL without receiving a subsequent alloHSCT remains unclear. "When patients were not able to receive bone marrow transplantation, there was only a very modest benefit from receiving imatinib," said Dr. Fielding. "Hence, it is likely that the long-term benefits of imatinib probably relate to a higher rate of alloegenic bone marrow transplantation."

3-Pronged Study

The current study was initiated in 1993 as a collaboration between the National Cancer Research Institute in the United Kingdom and the Eastern Cooperative Oncology Group in the United States. The objective was to assess the efficacy of alloHSCT in adult patients with ALL. The Ph+ arm of the trial is currently the largest single study of patients with Ph+ ALL, comprising 441 patients.

The first cohort in the study received treatment before the availability of imatinib (n = 266), and these data have been published. In March 2003, the protocol was modified, and a second cohort received imatinib 600 mg daily, which was added to the protocol as a consolidation block after the second induction chemotherapy (N = 86; "Late Imatinib").

Beginning in late 2005, a third cohort received imatinib earlier in the protocol, and it was combined with the second phase of induction (N = 89; "Early Imatinib"). In both the Late and Early groups, patients also received imatinib for an additional 2 years, after alloHSCT, if tolerated.

If alloHSCT was not possible, imatinib was permitted for 2 years, with maintenance. The trial closed to recruitment in December 2006 (United States) and October 2008 (United Kingdom), and only 8 patients to date have not completed therapy.

Dr. Fielding presented the results after a 3-year follow-up, which demonstrates large outcome differences between the 3 treatment cohorts.

Survival Advantages Observed

The researchers found that among patients who did not receive imatinib, overall survival reached 25%. This was compared with 34% in the Late Imatinib group and 48% in the Early Imatinib group.

Similar results were seen for event-free survival: 19% in the pre-imatinib group, 29% in the Late Imatinib group, and 35% in the Early Imatinib group. For relapse-free survival, the percentages were 36%, 45%, and 62%, respectively. The 3 groups were similar in terms of white blood cell counts and the presence of central nervous system disease at diagnosis, although the pre-imatinib cohort was younger as a result of an increase in the upper age limit for study entry.

An earlier start to imatinib is significantly better than a later start, the authors conclude, and there "can be no basis for omitting imatinib from the initial therapy of adult patients with Ph+ ALL."

The data show, however, that the best outcome is observed when patients receive imatinib followed by myeloablative alloHSCT, the researchers note. In this case, nearly 60% of such patients survive 3 years from diagnosis.

Use Varies Across the Globe

The use of imatinib in the treatment of Ph+ ALL is variable across the globe. "In some parts of the world it is a standard therapy," said Peter Emanuel, MD, director, Winthrop P. Rockefeller Cancer Institute, in Little Rock, Arkansas.

"But it is a new therapy in many parts of the world," said Dr. Emanuel, who served as press session moderator.

Dr. Fielding stated that imatinib is not widely available in London because all of the published evidence was early phase 1 and 2 evidence, short-term, and in a small population with short follow-ups. "That could not justify the expense of the drug," she said.

Jorge Cortes, MD, chair, CML Section, Department of Leukemia, University of Texas MD Anderson Cancer Center, in Houston, added that the situation is quite different in the United States. "Imatinib is used very routinely and commonly in ALL, in combination with chemotherapy, particularly in younger patients," he said. "In the older population, it is sometimes used alone or with minimum chemotherapy, but it is commonly used."

The authors have disclosed no relevant financial relationships. Dr. Cortes reports receiving research funding from ARIAD, Chemgenex, and Deciphera; Dr. Emanuel reports relationships with Bristol Myers Squibb, Novartis, and Genzyme.

American Society of Hematology 52nd Annual Meeting: Abstract 169. Presented December 5, 2010.

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