Over the past decade, significant advances have been made in the treatment of leukemia through the ongoing development of gene-based targeted therapies. Research presented today at the 52nd Annual Meeting of the American Society of Hematology (Orlando, December 4 ? 7, 2010) provides greater understanding of the optimal use of several BCR-ABL inhibitors for the treatment of acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML), and how a new gene target functions for several myeloid malignancies.

Commenting on the developments Peter Emanuel, MD, Director of the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock noted: “Each year, we continue to make significant strides in better understanding the underlying role certain genes play in the development of various forms of leukemia. These studies underscore the advances we are making to develop a new generation of treatment options that will improve overall outcomes for our patients.”

Acute lymphoblastic leukemia (ALL), a cancer of the white blood cells, is the most common type of leukemia, with about 3,930 new cases diagnosed each year in the United States. [1]. According to researchers, approximately 20 to 25% of all adults with ALL have a genetic abnormality in which some genetic material from chromosome 9 switches position with some genetic material from chromosome 22. This condition is known as Philadelphia chromosome-positive (Ph+) ALL, which is a rapidly progressive form of leukemia. It is associated with a poor prognosis since induction chemotherapy alone does not produce prolonged remissions. Therefore, an allogeneic stem cell transplant, in which a patient receives stem cells from a sibling or unrelated matched donor, is often recommended after the first complete remission.

Researchers discussing the significant advantages made in the treatment of (Ph+) ALL have demonstrated that the tyrosine kinase inhibitor (TKI) imatinib mesilate (Gleevec?/ Glivec?, Novartis) significantly enhances long-term outcomes [2] Today imatinib has become an integral part of front-line therapy for Ph(+) ALL, with remission rates exceeding 90% irrespective of whether imatinib is given alone or combined with chemotherapy. Treatment outcome with imatinib-based regimens has improved compared with historic controls, but most patients who do not undergo allogeneic stem cell transplantation (SCT) eventually relapse [3]

In 1993 researchers from the National Cancer Research Institute in the United Kingdom and the Eastern Cooperative Oncology Group (ECOG) in the United States initiated a study to evaluate whether allogeneic stem cell transplant is an effective treatment option for adult patients with Ph+ ALL. In this study, 266 patients received two phases of induction chemotherapy followed by an allogeneic stem cell transplant (“pre-imatinib” arm). Following the availability of imatinib, a targeted BCR-ABL inhibitor, the purpose of the study was modified in 2003 to include and evaluate the use of imatinib as part of consolidation therapy prior to an allogeneic stem cell transplant (“late-imatinib” arm) or as part of standard induction therapy prior to the transplant (“early-imatinib” arm). Results from the pre-imatinib cohort [4] were then used as a benchmark for use of imatinib in patients with Ph+ ALL.

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In the late-imatinib arm of the study, 86 patients received imatinib 600 mg a day as part of consolidation therapy prior to undergoing an allogeneic stem cell transplant following two induction chemotherapy regimens. Those in the early-imatinib arm (89 patients) were given imatinib 600 mg earlier as part of the second chemotherapy induction phase prior to the allogeneic stem cell transplant. All patients who received an allogeneic stem cell transplant in the study were given imatinib for two years post-transplant. If a transplant was not feasible for any reason, imatinib could be given as a maintenance therapy for two years.

Results from this study, the largest international study of patients with Ph+ ALL evaluating allogeneic stem cell transplantation (control group) and the use of imatinib, show significant differences in outcomes between the three different groups after three years of follow-up. The researchers found that overall survival reached 25% in the pre-imatinib arm, 34% in the late-imatinib arm, and 48% in the early-imatinib arm. Event-free survival was 19% in the pre-imatinib arm, 29% in the late-imatinib arm, and 35% in the early-imatinib arm. Additionally, relapse-free survival reached 36%, 45%, and 62% respectively.

Prior to the introduction and availability of imatinib, only 28% of patients went on to receive an allogeneic stem cell transplant per the study protocol. In these pre-imatinib patients, five-year overall survival was 40% for those patients who received an allogeneic stem cell transplant compared with 19% percent for non-transplanted patients. Of patients in the “late” and “early” arms who received imatinib, 44% were able to undergo the allogeneic stem cell transplant. Three-year overall survival was 59% for these transplant patients compared with 28% for those who did not receive a transplant.

“The Philadelphia chromosome is the single most common chromosome abnormality for adults with ALL, and therefore it is important to know that a targeted therapy like imatinib can help improve outcomes in these patients,” said lead study author Adele K. Fielding, MBBS, PhD, FRCPath, FRCP, Senior Lecturer, University College London. “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.”

[1] The Leukemia & Lymphoma Society. Acute Lymphocytic Leukemia . [Accessed December 4, 2010].
[2] Imatinib Significantly Enhances Long-Term Outcomes In Philadelphia Positive Acute Lymphoblastic Leukaemia; Final Results of the UKALLXII/ECOG2993 Trial 52nd Annual Meeting of the American Society of Hematology, December 4 ? 7, 2010, [Abstract 169][Accessed December 4, 2010]
[3] Ottmann OG, Pfeifer H. Management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
Hematology Am Soc Hematol Educ Program. 2009:371-81.

[4] Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood 2009 May 7;113(19):4489-96. Epub 2009 Feb 24.

Clinical trials
[5] Stem Cell Transplantation Compared With Standard Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia in First Remission NCT00002514

Additional information:
Fielding AK How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2010 Nov 4;116(18):3409-17. Epub 2010 Jul 23.

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