Novel therapies show promise against myeloid leukemia

December 06, 2003

(San Diego, Calif., December 6, 2003) - Leukemia, a cancer of the white blood cells, starts in the bone marrow but can spread to the blood, lymph nodes, and other organs. Because of its complexity and varying courses in each patient, the development of new and effective treatments for the disease has been challenging for scientists. According to research presented during the 45th Annual Meeting of the American Society of Hematology, novel therapeutic approaches directed against unique targets provide new hope for those suffering from these diseases.

"While the survival rate for leukemia has improved in the past two decades, especially among children, it is still a very difficult disease to treat in adults," said Richard Larson, M.D., University of Chicago Hospital. "New treatments are beginning to improve survival."

Probability and Impact of Obtaining a Cytogenetic Response to Imatinib as Initial Therapy for Chronic Myeloid Leukemia (CML) in Chronic Phase (Abstract 634)

Chronic myeloid leukemia (CML), a malignant cancer of the bone marrow, is one of the most common forms of leukemia. Imatinib (Gleevec), which blocks the abnormal protein driving the overproduction of abnormal white blood cells, has become the standard therapy for patients not undergoing stem cell transplantation. In newly diagnosed patients, researchers are still uncertain about the length of time imatinib should be administered to adequately determine a response. To assist patients and physicians in weighing the risks and benefits of continuing imatinib, this issue was recently examined by researchers from the Oregon Health & Science University Cancer Institute by analyzing data on 553 newly diagnosed chronic phase patients who were treated intitially with imatinib as part of a multi-national study that compared imatinib to interferon+Ara-C (cytosine arabinoside, the previous standard therapy for CML).

Scientists first determined whether varying levels of cytogenetic response were related to progression-free survival (PFS). Cytogenetic response measures the number of bone marrow cells that contain the Philadelphia chromosome, an abnormality that is unique to CML cells. The fewer cells that test positive for the Philadelphia chromosome, the better the cytogenetic response. At least 88 percent of patients who were = 35 percent positive for the Philadelphia chromosome (Ph) at three, six, or 12 months did not progress within 24 months after starting imatinib, and patients with a complete cytogenetic response (CcyR=0 percent Ph+) were least likely to experience disease progression.

Though achieving a complete response had a significant impact on long-term outcome, the time needed to achieve such a response had no effect on survival; the estimated PFS at 24 months was 96 percent (92-100) for patients with a complete response within the first three and six months, and 93 percent (88-97) for those who achieved a complete response only after six months.

Given the impact of response on survival, researchers decided to analyze the eventual likelihood of achieving a major and complete response. They noticed that if the patients were 66-95 percent Ph+ at three months, they had an estimated eight, 29, or 56 percent chance of achieving a complete response at six, 12, or 24 months after starting treatment, respectively. Patients who were >65 percent Ph+ at 12 months had only a nine to 14 percent chance of obtaining complete response at 24 months, while patients who were one to 35 percent Ph+ at any time point often achieved a complete response.

For this study, researchers defined disease progression as loss of a complete or major response (McyR== 35% Ph+), advancement to accelerated phase or blast crisis, or death during treatment. The three phases of CML are the chronic phase, the accelerated phase, and the blast crisis phase. As patients move through these phases, the prognosis worsens and patients experience increasing physical symptoms. Patients with poor cytogenetic assessments or with progression before the respective time point were not included.

"In addition to these results, the effect of increasing the dose of imatinib on the probability of attaining a major or complete response is being analyzed," said Brian Druker, M.D., of the Oregon Health & Science University Cancer Institute, the Howard Hughes Medical Institute, and lead author of the study. "We hope to confirm the reliability of cytogenetic responses and progression-free survival in patients developing major and complete responses with this therapy."

Leukemia is a cancer of the blood and the bone marrow in which certain blood cells become abnormal, yet the body continues to produce large numbers of these abnormal cells. Chronic myelogenous leukemia, or CML, is one type, referring to long-term cancer in which the body overproduces cancerous myeloid white blood cells.

Mesenchymal Progenitor Cells as Gene Delivery Systems for Cancer and Leukemia Therapy (Abstract 201)

Unlike hematopoietic (blood forming) stem cells, bone marrow-derived mesenchymal progenitor cells, or stem cells (MSC), can be intravenously injected into patients with leukemias and solid tumors without rejection. Scientists from The University of Texas M.D. Anderson Cancer Center explored the potential of human MSC to carry therapeutic genes into tumors and examined whether MSC producing interferon-beta can inhibit the growth of metastatic tumors in the lungs of immunodeficient mice. The interferon was produced by MSC after their infection with a virus carrying the interferon-beta gene. Immunodeficient mice are used for transplantation and the study of human cancers and leukemias.

Upon infecting MSC with interferon-beta (IFNß), the IFNß-MSC directly inhibited the growth of both melanoma and breast carcinoma cells in experiments in vitro (in tissue cultures). When researchers intravenously (IV) injected IFNß-MSC (four doses of 106 MSC/week) into mice with metastatic lung cancers, tumor growth was inhibited and survival of the animals doubled. A key finding was that IV-injected MSC hone and proliferate selectively in the stroma and metastases of tumors, and have the potential to produce therapeutic agents locally. MSC were also found to be capable of delivering replication-competent oncolytic adenovirus (delta24, a virus capable of destructing tumor cells) into tumors. Thus, MSC act as "Trojan horses" that carry therapeutic genes into the tumors. In contrast, when IFNß was injected subcutaneously, no tumor inhibition was observed.

Similar results were seen after intraperitoneal injections (into the lining of the abdominal cavity) of IFNß-MSC into mice with ovarian cancer, doubling survival in SKOV-3 and curing 70 percent of mice with OVAR-3 cancers. Interestingly, MSC injected into the carotid artery of mice with malignant gliomas (incurable brain tumors) reproduced selectively in the tumors, and not in normal brain tissues. Tumor growth was inhibited by co-cultures of IFNß-MSC and glioma cells in vitro, and injection of IFNß-MSC directly into the tumor in vivo. In a model of very aggressive chronic myeloid leukemia in blast crisis, MSC-produced interferon alpha (IFNaMSC) inhibited tumor growth in vivo and doubled the survival rates of CML bearing mice.

"These findings indicate that mesenchymal stem cells can deliver interferons, oncolytic adenovirus, and perhaps other therapeutic agents directly into tumor and leukemia sites," said Michael Andreeff, M.D., Ph.D., of the M.D. Anderson Cancer Center, lead author of the study. "MSC appear to selectively grow and deliver payload at tumor sites, suggesting strong potential of gene-manipulated mesenchymal progenitor cells for targeted cancer and leukemia therapies in the future."

Induction/Maintenance with ATRA/ As2O3 Combination Yields a High Quality Clinical/Molecular Remission and Disease-Free Survival in Newly Diagnosed Patients with Acute Promyelocytic Leukemia (Abstract 486)

All-trans retinoic acid (ATRA, found in vitamin A) and arsenic trioxide (As2O3, an inorganic chemical compound) have separately been proven very effective in treating acute promyelocytic leukemia (APL). In an attempt to further improve rates of clinical remission (CR) and long-term disease-free survival (DFS), researchers at the Shanghai Institute of Hematology recently compared different therapeutic regimens in which ATRA and As2O3 were applied either jointly or solely in combination with chemotherapy.

In the study, 61 newly diagnosed APL patients were randomly assigned to one of three treatment groups: ATRA, As2O3, and the combination of the two, for remission induction and maintenance therapy. Chemotherapy also was used for patients with high white blood cell counts. Based on the study results, the ATRA/As2O3 combination offers superior results for remission/maintenance therapy of APL compared to the sole use of either drug alone.

Although CR rates in all three groups were high (>90 percent), the time to achieve CR differed significantly. The combination therapy group required the shortest amount of time to achieve a CR, and also experienced more rapid recovery of the white blood cell and platelet counts. The disease burden at CR decreased more significantly after combined therapy as compared to ATRA or As2O3 monotherapy. All 20 patients in the combination therapy group remained in CR while seven of 37 patients treated with monotherapy relapsed after a follow-up of eight to 30 months.

"This new approach may make APL a curable disease in most cases," said Sai-Juan Chen, M.D., of the Shanghai Institute of Hematology, corresponding author of the study.

The authors suggest that the combination of ATRA and As2O3 has a joint effect on apoptosis (cell death) and degradation of PML-RAR alpha oncoprotein and this synergy might provide a plausible explanation for superior efficacy. Side effects, especially liver dysfunction, were not increased by the combination of ATRA and As2O3, as compared to monotherapy.

Acute promyelocytic leukemia is a rapidly progressing cancer in which the predominant abnormal blood cell type is the malignant promyelocyte, a bone marrow cell in a developmental stage between a myeloblast (a large mononuclear marrow cell) and a myelocyte (a marrow cell that gives rise to the mature white blood cells in the circulation, called granulocytes). The promyelocytic leukemia gene (PML), which is involved in the control of apoptosis, is fused to the retinoic acid receptor alpha (RARa) gene in PML patients. The PML-RARa oncoprotein is present only in the leukemia cells and inhibits the normal function of PML.

The American Cancer Society estimates that, in 2003, there will be about 30,600 new cases of all types of leukemia in this country, and about 2,600 people will die of chronic leukemia.
The American Society of Hematology is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

American Society of Hematology

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