Jan. 28, 2011 Over the past decade, significant advances have been made in the treatment of leukemia through the ongoing development of gene-based targeted therapies. Research recently presented at the 52nd Annual Meeting of the American Society of Hematology 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.
"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," said moderator of the press conference Peter Emanuel, MD, Director of the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock. "These studies underscore the advances we are making to develop a new generation of treatment options that will improve overall outcomes for our patients."
Imatinib Significantly Enhances Long-Term Outcomes in Philadelphia Positive Acute Lymphoblastic Leukemia; Final Results of the UKALLXII/ECOG2993 Trial
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. According to researchers, approximately 20 to 25 percent 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.
In 1993 researchers from the National Cancer Research Institute in the United Kingdom and the Eastern Cooperative Oncology Group 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 (Fielding, Blood 2009) were then used as a benchmark for use of imatinib in patients with Ph+ ALL.
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 percent in the pre-imatinib arm, 34 percent in the late-imatinib arm, and 48 percent in the early-imatinib arm. Event-free survival was 19 percent in the pre-imatinib arm, 29 percent in the late-imatinib arm, and 35 percent in the early-imatinib arm. Additionally, relapse-free survival reached 36 percent, 45 percent, and 62 percent respectively.
Prior to the introduction and availability of imatinib, only 28 percent 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 percent 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 percent were able to undergo the allogeneic stem cell transplant. Three-year overall survival was 59 percent for these transplant patients compared with 28 percent 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."
Excellent Outcomes at 3 Years With Nilotinib 800 mg Daily in Early Chronic Phase, Ph+ Chronic Myeloid Leukemia (CML): Results of a Phase 2 GIMEMA CML WP Clinical Trial
It is estimated that the incidence rate of chronic myeloid leukemia (CML), a type of blood and bone marrow malignancy in which too many white blood cells are produced, varies from 0.6 to 2 cases per 100,000 persons each year. More than 95 percent of people with CML are affected with the Philadelphia chromosome (Ph+), a unique chromosomal abnormality that harbors a leukemic gene called BCR-ABL. This gene promotes the disease and allows the disease to progress to terminal acute leukemia -- defined as "accelerated" and "blast" phase -- if the disease is not properly treated. The current standard first-line treatment for Ph+ CML is the targeted BCR-ABL inhibitor, imatinib.
Nilotinib, a second-generation BCR-ABL inhibitor, recently received FDA approval (June 2010) as a first-line therapy for this patient population based on the results from an 18-month study that found that nilotinib demonstrated superior efficacy as compared with standard therapy imatinib, with higher and faster molecular responses. This study also showed that rates of progression to accelerated or blast phase were also significantly lower for nilotinib than for imatinib.
In order to confirm that the efficacy of nilotinib is durable over a three-year time frame, the period of time when most of the failures to imatinib are described, researchers from the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Chronic Myeloid Leukemia (CML) Working Party (WP) in Italy enrolled 73 patients with newly diagnosed Ph+ CML into a phase II clinical trial in which patients received nilotinib 400 mg twice daily. Currently, the median follow-up is longer than three years. The primary endpoint of the study was the complete cytogenetic response (CCgR) rate at 12 months -- meaning that no cells containing the Philadelphia chromosome were detected in the bone marrow. Other outcomes evaluated in the study included overall survival, progression-free survival, failure-free survival, and event-free survival.
At different key milestones throughout the study, the CCgR rate was high (78 percent at three months, 96 percent at six, 12, and 18 months). Within 12 months, the cumulative CCgR rate for study participants was 100 percent, which means that all patients achieved CCgR at least once. Additionally, after a median follow-up of 36 months, overall survival, progression-free survival, and failure-free survival reached 99 percent for each, and event-free survival was 92 percent. The cumulative major molecular response (MMR) rate, a more sensitive measurement of response, was 96 percent at 12 months. The MMR rate was 52 percent at three months, 66 percent at six months, 85 percent at one year, 81 percent at 18 months, and 82 percent at two years. In patients who achieved an MMR, none progressed to accelerated or blast phase CML. Furthermore, only one patient in the entire study progressed to accelerated or blast phase due to the development of another BCR-ABL mutation called a T315I mutation.
"While it is important to rapidly induce responses in these patients, it is also important that these responses last as long as possible," said lead study author Gianantonio Rosti, MD, Scientific Secretary of the GIMEMA CML WP, Department of Hematology and Oncology, University of Bologna, Bologna, Italy. "Results from this study not only show that nilotinib quickly induces high rates of response, but responses also are durable and stable beyond three years, translating into optimal outcomes for newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia."
A Phase I Trial of Oral Ponatinib (AP24534) in Patients With Refractory Chronic Myelogenous Leukemia (CML) and Other Hematological Malignancies: Emerging Safety and Clinical Response Findings
Despite the recent advances in the treatment of chronic myeloid leukemia (CML) over the past decade with both first- and second-generation BCR-ABL inhibitors, there are patients who continue to fail two or more of these therapies and/or develop a mutation called T315I, which alters the shape of the ABL enzyme, making these patients unresponsive to current therapies. Currently, there are no effective treatment options for patients who develop a T315I mutation. Pre-clinical research has demonstrated that ponatinib, an investigational pan-BCR-ABL inhibitor, may inhibit the entire spectrum of mutations that cause resistance to other BCR-ABL inhibitors.
Researchers at The University of Texas MD Anderson Cancer Center in Houston, in collaboration with colleagues from other institutions in the United States, initiated an open-label, dose escalation phase I study to assess the safety and investigate the anti-leukemic activity of ponatinib. A total of 67 patients with various refractory hematologic malignancies including CML, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML), were enrolled in the study to receive a daily oral dose of ponatinib. A large majority of patients with Ph+ CML had previously failed treatment with other BCR-ABL inhibitors (imatinib: 96 percent, dasatinib: 89 percent, nilotinib: 55 percent, more than two previous therapies: 95 percent, and more than three previous therapies: 64 percent). Additionally, 72 percent of all patients enrolled in the study had BCR-ABL mutations, with 38 percent (23 patients) having a T315I mutation and 12 percent (7 patients) having an F317L mutation.
To date, patients enrolled in the study have received up to 60 mg doses of ponatinib with 64 percent (43 patients) remaining on therapy and 36 percent (24 patients) discontinuing therapy. Of 32 evaluable patients with CML in chronic phase, 30 patients (94 percent) had a complete hematologic response (meaning blood cell counts are in the normal range), and 20 patients (63 percent) had a major cytogenetic response (meaning that no cells containing the Philadelphia chromosome were detected in the bone marrow). Of those achieving a major cytogenetic response, 12 patients had a complete cytogenetic response and eight patients had a partial cytogenetic response. Eighteen of these patients remained on ponatinib for a mean duration of 326 days without progression (range 142 to 599 days) with 13 of these patients having a confirmed response at a second assessment.
Of 11 evaluable patients with CML in chronic phase with a T315I mutation, 11 patients (100 percent) achieved a complete hematologic response and nine patients (82 percent) had a major cytogenetic response (eight of these patients had a complete cytogenetic response). Of 16 evaluable patients with either CML in accelerated or blast phase or with Ph+ ALL, five patients (31 percent) had a major hematologic response, three patients (19 percent) had a major cytogenetic response, and one patient (6 percent) had a minor cytogenetic response. Of nine evaluable patients with CML in accelerated or blast phase or patients with Ph+ ALL with a T315I mutation, three patients (33 percent) had a major hematologic response, and two patients (20 percent) had a major cytogenetic response.
Responses also were seen in heavily refractory patients with no mutations as well as in patients with other mutations who were resistant to currently approved tyrosine kinase inhibitors. For example, there was one complete cytogenetic response and one partial cytogenetic response in two patients with an F317L mutation who had previously failed therapy with imatinib, dasatinib, and nilotinib. Another patient with an F359C mutation who failed both imatinib and nilotinib therapy achieved a complete hematologic response and a complete cytogenetic response with ponatinib. Overall, 13 out of 60 patients (22 percent) with Ph+ disease achieved a major molecular response, including 12 out of 42 patients (28 percent) with CML in chronic phase and six out of 15 patients (40 percent) with T315I mutation confirmed at the start of the study. Twelve major molecular responses occurred in patients who received ponatinib for four months or less. There were four major molecular responses in patients who received ponatinib for only two months or less. Major molecular responses also were seen in patients with the following mutations: M351T, F359C, F317L, M244V, and G250E.
"These results are exciting because it is very difficult to induce responses, particularly at the high rates seen with ponatinib, in heavily refractory patients," said lead study author Jorge Cortes, MD, Deputy Chair and Professor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center in Houston. "While these results need to be confirmed in a larger study, ponatinib may be the next step in coming closer to overcoming, and possibly preventing, the most difficult mechanisms of resistance in CML, and ultimately finding a cure for Philadelphia chromosome-positive leukemias."
Impaired Hydroxylation of 5-Methylcytosine in TET2 Mutated Patients With Myeloid Malignancies
In previous research, mutations in the TET2 (Ten-Eleven Translocation-2) gene were found across a broad range of myeloid malignancies, but little is known about the pathologic consequences of this mutation or the role it plays in the development of diseases such as myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia.
A team of scientists at the Taussig Cancer Institute at the Cleveland Clinic in Ohio and Dana-Farber Cancer Institute at Harvard University initiated several specialized experiments on leukemic cancer cells carrying TET2 gene mutations. TET2 mutations occurred throughout the entire TET2 gene and led to its inactivation. Functional studies showed that the TET2 mutations likely alter epigenetic regulation.
Epigenetic alterations are a form of chemical modification of the DNA strand that naturally occurs during normal tissue maturation, but is disturbed in cancer. One key epigenetic mechanism is the methylation of cytosines (one of the four building blocks of DNA), which effectively blocks or "silences" particular genes.
Experimental results demonstrate that the TET2 gene alters the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, which likely in turn affects the silencing function of 5- methylcytosine. TET2 mutations, or experimentally decreased TET2 levels, resulted in lower hydroxymethylcytosine levels and perturbed maturation of bone marrow stem cells.
"The process of methylation or 'silencing' of genes can be altered in disease or through application of epigenetic drugs. Identification of the variant of cytosine, 5-hydroxymethylcytosine, introduces a new mechanism of epigenetic regulation that has never been explored," said senior study author Jaroslaw P. Maciejewski, MD, PhD, FACP, Chairman, Department of Translational Hematology and Oncology Research, Taussig Cancer Institute at the Cleveland Clinic in Ohio. "The mutation in TET2 is an important, common mutation associated with leukemia that affects epigenetics, and now we are closer to deciphering the functional consequences of this mutation. It is likely that 5-hydroxymethylcytosine levels may become a disease biomarker and possibly molecular target for the development of new therapies."
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