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Advances in Genetics and Treatment Protocols Lead to Significant Progress in Leukemia and Myeloproliferative Disorders

Advances in Genetics and Treatment Protocols Lead to Significant Progress in Leukemia and Myeloproliferative Disorders

Research presented at the 51st Annual Meeting of the American Society of Hematology (ASH) in New Orleans introduced potential new treatment options and improved diagnostic methods for patients suffering from acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), infant acute lymphoblastic leukemia (ALL), and myelofibrosis that are based on a better understanding of the underlying genetic causes of these conditions.

APL in Developing Countries
In developed countries, the standard treatment for APL is a combination of all-trans retinoic acid (Tretinoin, Vesanoid) and an anthracycline-based chemotherapy; this results in a 5-year overall survival rate of approximately 90%. The morbidity and mortality of APL in patients in developing countries is significantly higher. Researchers from the International Consortium on Acute Promyelocytic Leukemia (IC-APL), an initiative of the American Society of Hematology, aimed to reduce this difference in survival. They have made progress through the IC-APL’s international network of clinicians and researchers dedicated to accelerating patient diagnosis and delivering prompt treatment through the implementation of evidence-based guidelines in developing countries (abstract 6).

In this study, any patient suspected of having APL was immediately started on all-trans retinoic acid, while bone marrow samples were sent to a central laboratory in order to confirm the diagnosis quickly. A total of 102 patients (70 in Brazil, 25 in Mexico, and 7 in Uruguay) were enrolled and received treatment identical to the LPA 2005 protocol set forth by the PETHEMA working group of the Spanish Association of Hematology and Hemotherapy, which consisted of all-trans retinoic acid, idarubicin, mitoxantrone, and cytarabine combination therapy. In this study, however, patients received the more affordable daunorubicin instead of idarubicin.

The study found that participation in the IC-APL resulted in an approximately 40% decrease in early mortality and a marked improvement in the long-term outcome of patients with APL to levels similar to those reported in developed countries. A total of 77 patients (79%) achieved a complete remission, and 1-year overall and disease-free survival from the date of complete response was 95%.

“It is unfortunate that even with the availability of effective treatment options, in developing countries, patients with acute promyelocyctic leukemia are not receiving prompt treatment and thus face higher mortality rates than those in developed countries,” said lead author Eduardo M. Rego, MD, PhD, professor of the Medical School of Ribeiro Preto at the University of So Paulo in Ribeiro Preto, Brazil. “The IC-APL protocol is an affordable program that has radically changed the fate of these patients through the implementation of simple measures and international collaboration between doctors.”

Omacetaxine in Imatinib-Resistant CML
Over the past several years, tyrosine kinase inhibitors, that target BCR-ABL have become standard therapy for the treatment of CML. However, there is a small subset of patients who do not respond to tyrosine kinase inhibitors because they have an additional mutation called BCR-ABL T315I. For these patients, there are currently no approved treatments. Led by researchers from The University of Texas M. D. Anderson Cancer Center in Houston, the study evaluated the safety and efficacy of omacetaxine in patients with CML who have the T315I mutation and are resistant to first-line imatinib (Gleevec) therapy. Given by subcutaneous injection, omacetaxine is a potential treatment for CML with a unique mechanism of action that is independent of tyrosine kinase inhibition (abstract 644).

A total of 90 patients were enrolled, with data available for analysis on 66 patients: 40 in chronic phase, 16 in accelerated phase, and 10 in blast phase CML with a confirmed BCR-ABL T315I mutation. All patients had previously failed imatinib therapy. In addition, 79% had also failed therapy with at least one more tyrosine kinase inhibitor. Patients were started on cycles of 1.25 mg/m2 of omacetaxine twice daily for 14 days, to be repeated every 28 days until a hematologic response was achieved. Once a response was demonstrated, patients received 1.25 mg/m2 of omacetaxine twice daily for 7 days, approximately every 28 days as maintenance therapy.

The study demonstrated that omacetaxine produced both strong hematologic responses and cytogenetic responses with a safety profile consisting mainly of hematologic toxicities. Specifically, median overall survival was 18.8 months for accelerated-phase patients and 1.8 months for blast-phase patients, while median overall survival for chronic-phase patients had not yet been reached. Median time to disease progression was 11.2 months for chronic-phase, 3.1 months for accelerated-phase, and 1.2 months for blast-phase patients.

“Omacetaxine is the first drug to show consistent activity in patients with chronic myeloid leukemia who are affected with the T315I mutation,” said lead author Jorge Cortes, MD, internist and professor, deputy chair, department of leukemia, division of cancer medicine, The University of Texas M. D. Anderson Cancer Center in Houston. “Our findings show that omacetaxine may be a viable treatment option for this patient population that currently has no other available drug therapies.”

INCB018424 in Myleofibrosis
There are no approved treatment options for patients with myelofibrosis, and average life expectancy is 5 to 7 years. Recent evidence indicates that exaggerated Janus activated kinase (JAK) signaling plays an important role in the pathogenesis of myelofibrosis. Researchers at The University of Texas M. D. Anderson Cancer Center in Houston examined INCB018424, an investigational oral selective inhibitor of JAK1 and JAK2 enzymes, to determine its safety and effectiveness as a treatment option for these patients (abstract 756). Preliminary results (Verstovsek, ASH 2008) had demonstrated that INCB018424 may shrink enlarged spleens and improve other disease-related symptoms in patients with myelofibrosis.

Study authors enrolled 155 patients with either primary myelofibrosis or myelofibrosis occurring after polycythemia vera, or essential thrombocythemia. Patients received an individually optimized dose of 10, 15, or 25 mg of INCB018424 twice a day. Efficacy of INCB018424 was assessed by magnetic resonance imaging (MRI) measurements of spleen size at 1, 3, and 6 months. To measure the effect of INCB018424 on myelofibrosis-related symptoms, patients were surveyed about the impact of the treatment on their health and well-being. The impact of INCB018424 on exercise capacity was measured with a standardized 6-minute-walk test at the start of the study and after 1, 3, and 6 months of therapy.

The data revealed that an individually optimized dosing regimen of INCB018424, with starting doses of 10 or 15 mg twice a day and increased or decreased doses depending on each patient’s needs, resulted in improved quality of life and disease symptoms, reduction in spleen size, and a better hematologic safety profile than previously observed at a higher starting dose of 25 mg twice-a-day (maximum tolerated dose). Treatment with INCB018424 resulted in a rapid reduction of spleen volume and was evident as early as 1 month and lasted beyond 6 months of therapy. Specifically, 48% of patients had spleen volume reduction of greater than or equal to 35% after 6 months of treatment. Treatment with INCB018424 also resulted in improvements in the 6-minute-walk test, with median increases from baselines of 33, 58, and 70 meters after 1, 3, and 6 months of therapy, respectively. Spleen response was associated with greater improvements in exercise capacity and reduced fatigue. Finally, a great majority of patients improved their health and well-being while on therapy with INCB018424.

“Myelofibrosis is a serious disease that has few therapeutic options,” said lead author Srdan Verstovsek, MD, PhD, associate professor, department of leukemia, division of cancer medicine, The University of Texas M. D. Anderson Cancer Center in Houston. “While the treatment approach for these patients has been mostly in the form of palliative care, INCB018424 may provide patients with the first-ever treatment option that is designed to work on the underlying cause of this disease.”

Genetics of Infant ALL
Infants with leukemia are among the most challenging populations to treat in all of pediatric oncology. Leukemia, of which the most common form in children is ALL, is the most widespread cancer in children and in infants less than 1 year old. Most infants less than 1 year old with ALL respond poorly to chemotherapy drugs and have a much lower survival rate than do older children. One factor associated with poor outcomes in infant ALL is the MLL translocation, a molecular abnormality in which the MLL gene on chromosome 11 breaks and then becomes joined with one of a number of different “partner” genes on other chromosomes. In collaboration with the Children’s Oncology Group (COG), researchers from the Children’s Hospital of Philadelphia determined the specific partner genes involved in MLL translocations among cases of ALL in infants enrolled in the clinical trial COG P9407 for the treatment of infant ALL (abstract 907). The researchers then assessed how different MLL partner genes affected outcome and studied how they were related to other classical prognostic factors, including age and white blood cell count at diagnosis.

A total of of 221 infants with ALL were enrolled in the COG P9407 trial. Researchers used several methods (eg, Southern blot analysis, reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization) to identify MLL translocations and specific partner genes at the levels of the genes and chromosomes. Statistical tests were then used to determine how MLL translocations with different partner genes affected the prognosis, and their relationships to classical prognostic factors.

The COG researchers found that the leukemia cells of 74% of infants with ALL had an MLL translocation and that the most common partner genes of MLL were AF4, ENL, and AF9. The two most common partner genes of MLL, AF4 (located on chromosome 4) and ENL (located on chromosome 19), negatively affected patient survival. Better outcomes were observed when the MLL gene fused with AF9, located on chromosome 9. The outcome was far worse when AF4 or ENL occurred as partner genes in MLL translocations in cases of ALL in younger infants who were less than 90 days old at diagnosis. In addition, translocations fusing MLL with AF4 were associated with a higher white count, whereas translocations fusing MLL with AF9 were associated with a lower white blood cell count. These new associations of specific MLL partner genes with age and white blood cell count indicate how disease biology and the classical prognostic factors in infant ALL are integrally connected.

“The ability to characterize acute lymphoblastic leukemia based on specific partner genes may provide a new way to determine whether infants with ALL in which the partner genes of MLL are different will benefit from specific types of treatment,” said senior author Carolyn A. Felix, MD, professor of pediatrics at the Children’s Hospital of Philadelphia.
 

 
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