(Laurie Barclay, MD)

Leukemia is a cancer of white blood cells originating in the bone marrow. Malignant transformation can occur at any stage of blood cell development. Based on their cell of origin, leukemias can be classified into myelogenous leukemias if granulocytes or monocytes are affected, or as lymphocytic leukemias. In the U.S., annual incidence of leukemia is about 31,000 new cases.

In acute leukemias, which have a rapid onset, the malignant blast cells are immature and lack normal immune functions. When these cells enter the blood, they may metastasize to the lymph nodes, brain, spinal cord, liver, and/or testes. If untreated, survival in acute leukemia is typically less than a few months. Some subtypes of acute leukemia respond well to treatment and many patients are cured, while other types of acute leukemia have a less favorable outcome.

Chronic leukemias involve proliferation of more mature cells, which retain some immune function. Because these abnormal cells multiply more slowly than do blast cells, onset is typically more gradual. Chronic leukemia cells have a much longer survival than normal white blood cells, resulting in accumulation of mature granulocytes or lymphocytes in excess.

Acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL) are the most common types in adults. In AML, the bone marrow produces too many blast cells, or immature white blood cells which normally differentiate into granulocytes, at the expense of healthy red and white blood cells and platelets. Acute lymphocytic leukemia (acute lymphoblastic leukemia; ALL) is diagnosed primarily in children, whereas chronic myelogenous leukemia (CML) is diagnosed primarily in adults.

Symptoms of anemia include fatigue, fevers or night sweats, shortness of breath and pallor. Shortage of normal white blood cells and an excess of leukemic blast cells may result in increased infections, bone or joint pain. Thrombocytopenia is associated with increased bleeding, for example swollen and bleeding gums, nose bleeds, easy bruisability, petechiae, and cuts that heal slowly or bleed more easily than usual. Some individuals with AML may be asymptomatic and diagnosed by an abnormal blood count.

Physical findings may include lymphadenopathy or an enlarged spleen. The diagnosis is confirmed by bone marrow biopsy and microscopic examination of leukemic cells to determine the type of leukemia from immunologic markers, histochemical staining, and cytogenetics. In AML, there are seven sub-types varying in their response to different treatments, so typing offers important information for prognosis and management.

Chemotherapy regimens for leukemia usually contain multiple drugs, each acting on a different part of the cell cycle to increase efficacy and decrease resistance. Currently available immunotherapeutic agents include interferon alpha, which occurs naturally in some cells, and monoclonal antibodies targeting tumor-specific proteins. Gemtuzumab (MylotargTM), which uses a monoclonal antibody to deliver a toxin called calichearnicin, was recently approved for treating some forms of leukemia.

Differentiation therapy such as T-retinoin induces leukemic blast cells to resume their normal life cycle, mature and differentiate into benign cell types.

Because treatment for leukemia may suppress blood cell counts and thereby increase risk of infection, supportive care may include antibiotics, transfusions of red blood cells and platelets, and blood cell growth factors such as granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF).

CenterWatch has identified 31 drugs in the leukemia pipeline in various phases of development, including cell cycle inhibitors, monoclonal antibodies, and other immunotherapeutic agents.

Trisenox (arsenic trioxide) is currently FDA approved for specific indications in acute promyelocytic leukemia (APL), and Cell Therapeutics is now conducting phase III testing for further indications in more than 60 clinical trials. This drug is believed to kill cancer cells through apoptosis, or programmed cell death. It is now indicated for induction of remission and consolidation in patients with APL refractory to, or relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the t(15;17) translocation or PML/RAR-alpha gene expression.

In this population, clinical response rate is 70%-75%, with an 82% molecular remission rate in patients who achieve clinical response. With consolidation and maintenance therapy, there are further increases in molecular remission rate. Overall 18-month survival is 66%.

Genta is conducting a Phase III trial of Genasense (oblimersen, G3139) in CLL. This drug targets the Bcl-2 protein, which is overexpressed in many cancers. In this trial, patients who have relapsed from other therapies are randomized to standard treatment alone, consisting of cyclical treatment with fludarabine and cyclophosphamide, or to Genasense added to standard treatment.

Ceplene, a histamine-2 receptor agonist in Phase III testing by Maxim Pharmaceuticals, is co-administered with other immunotherapeutic agents. More than 2000 patients have participated in completed and ongoing clinical trials in a variety of cancers and liver diseases, including one Phase III trial in AML.

The mechanism of action of Ceplene is to reduce oxidative stress by preventing the production and release of oxygen free radicals, thereby protecting immune cells that defend against cancer, including Natural Killer (NK) cells, cytotoxic T cells, and Natural-Killer/T cells (NK/T cells). This protection allows other immunotherapies, such as interleukin-2 (IL-2) and interferon- alpha (IFN-alpha), to better activate NK cells, T cells and NK/T cells, thus enhancing the killing of tumor cells.

Antigenics is in Phase II testing of AG-858, a personalized vaccine based on heat shock protein 70 (HSP70) and made from individual patients' cancer cells. This approach is designed for efficacy while minimizing side effects. White blood cells are collected from each patient by leukapheresis and sent to Antigenics to manufacture the personalized vaccine, which is administered on an outpatient basis over the course of several weeks.

In an ongoing pilot study of an earlier HSP70-based vaccine, seven of eight patients evaluated had positive responses, and vaccination was associated with an increased production of interferon gamma suggesting T-cell activation. In a Phase II trial, Antigenics is evaluating the safety and efficacy of combination treatment with AG-858 in patients with chronic phase CML who have not achieved complete clinical response to Gleevec.

Another vaccine, also in Phase II testing, is the Cell Genesys product Gvax. Irradiated tumor cells from each patient are genetically modified to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), a hormone that stimulates the immune response to vaccines. The goal of Gvax therapy is to stimulate an immune response directed against the patient's own tumor and to enhance the anti-leukemic activity of standard chemotherapy and transplantation.

Preliminary data from a multicenter Phase II trial enrolling 54 patients indicate that vaccine therapy is well tolerated and may reduce residual leukemic cells that survive chemotherapy. In this trial, eight of 12 patients tested after vaccine therapy had decreased bone marrow levels of WT-1, a leukemia-associated genetic marker detectable in over 95% of patients with active AML. Patients were first treated with chemotherapy to induce a complete remission and were then vaccinated before and after autologous bone marrow stem cell transplantation.

Animal studies also suggest that Gvax administered after bone marrow transplantation significantly prevented tumor relapse. Tumor-free survival rates were 80% in animals receiving Gvax in addition to transplantation, 40% in animals receiving vaccination alone, and 0% in untreated animals. Gvax-treated animals also had an expanded population of tumor-specific immune cells.

Ceflatonin (homoharringtonine) is in Phase II development by ChemGenex Therapeutics. This angiogenesis inhibitor also affects upregulation of genes associated with apoptosis, or programmed cell death. In pilot studies, Ceflatonin treatment was associated with a 60% complete response rate in CML. Because Ceflatonin has already demonstrated good clinical activity for all stages of CML, ChemGenex believes it has a high probability of FDA approval, initially for an intravenous and eventually for an oral formulation. A Phase II study is now evaluating Ceflatonin to treat CML patients in remission, and additional studies in AML are scheduled for early 2004.

Clofarex (clofarabine) is a next-generation purine nucleoside antimetabolite in Phase II testing by ILEX Oncology. In October 2003, ILEX submitted a New Drug Application (NDA) to the FDA for clofarabine for the treatment of refractory or relapsed acute leukemias in children. In a Phase I trial, adults over the age of 50 years with acute leukemia are receiving the combination of clofarabine and ara-C.

Although vincristine has long been an old standby in chemotherapy, Inex Pharmaceuticals has given it a new twist in its Phase I/II product Onco TCS, which is vincristine encapsulated in a Transmembrane Carrier System (TCS). Drug delivery via liposomes allows prolonged blood circulation, tumor accumulation and extended drug release at the cancer site, thereby potentially increasing efficacy and reducing the side effects of the encapsulated drug. A Phase II trial is underway in relapsed ALL.

Point Therapeutics is in Phase I-II development of PT-100, which stimulates production of cytokines and chemokines that promote innate immunity. In addition to being well-tolerated in Phase I safety studies, it may be effective in hematologic malignancies while relieving chemotherapy-induced neutropenia. An ongoing Phase I/II clinical study is testing PT-100 in combination with RituxanŽ in patients with CLL.

In a Phase I chemotherapy-induced neutropenia study of seven patients, PT-100 at a daily dose of 800 micrograms administered on the second through the eighth day following the administration of chemotherapy was associated with a median improvement of two days in the duration of severe neutropenia and with a 60% median reduction in the duration and severity of neutropenia.

A novel approach is Theralux stem cells therapy, in Phase I/II testing in CML by Celmed BioSciences. Stem cells from the patient are treated with the photosensitive molecule TH 9402 and a light source to eradicate malignant cells. This procedure allows autologous stem cell transplantion without the risk of transplanting remaining leukemic cells. Theralux may also have potential advantages in allogenic transplantation to prevent graft-versus-host disease.

As new technologies proliferate in cytogenetics and molecular biology, there may continue to be a logarithmic expansion in novel treatment approaches to the leukemias. Time will tell which of these strategies prove to be most effective and least toxic, either alone or in combination.