Several areas of research have resulted in new approaches to the treatment of leukemia, lymphoma and myeloma.

New Drug Development
Immunotherapy
Reversal of Multidrug Resistance
Gene Therapy
Blood and Marrow Transplantation


New Drug Development
In the last decade, several very important new drugs and new uses for existing drugs have greatly improved cure rates or remission duration for some patients with leukemia. 

Imatinib mesylate (Gleevec®) is now the drug of choice in newly diagnosed patients with chronic myelogenous leukemia (CML). It works by blocking the oncogene-encoded protein product that instigates the transformation to a leukemic cell. The protein is an enzyme in the family of tyrosine kinases.  Gleevec offers several advantages to patients, including oral administration, decreased side effects, little if any adverse effect on normal tissues and a high response rate. The effectiveness and tolerance of older patients and the projections from the first five years of clinical trials in newly diagnosed patients suggest that the drug will prolong the duration of hematological remission and life when compared to former therapy. Although a minority of patients have developed resistance to the drug, two second-generation agents, dasatinib and nilotinib, are entering clinical use that can overcome this resistance in some cases. Gleevec is not only a very important new agent in the treatment of CML, but it can also induce remissions in some cases of acute leukemia, chronic eosinophilic leukemia (formerly hypereosinophilic syndrome), occasional cases of chronic myelomonocytic leukemia (CMML) and in systemic mastocytosis because they have a genetic abnormality that results in an abnormal tyrosine kinase that is blocked by imatinib (mutant ABL, PDGFR or KIT).

The treatment of hairy cell leukemia, a less common type of chronic lymphocytic leukemia (CLL), has improved dramatically with the introduction of two very useful agents - pentostatin and most notably, cladribine. Hairy cell leukemia had been very resistant to treatment; however, cladribine has been very effective in producing long-term remissions of the disease after only one week of therapy.

The remission rate and duration of remission of acute promyelocytic leukemia (APL) has been improved significantly with the introduction of all-trans retinoic acid as a complement to chemotherapy. Arsenic trioxide is another drug available to treat this subtype of acute leukemia. Early studies indicate the combination of arsenic trioxide and all-trans retinoic acid may be a further advance in the initiation of therapy.

In May 2006, thalidomide (Thalomid®)), in combination with dexamethasone, was approved by the FDA for newly diagnosed myeloma. Two additional drugs being studied in clinical trials have shown responses in a subset of patients
with myeloma: the proteasome inhibitor bortezomib (Velcade®) and the immune modulator (Revlimid). Velcade is approved by the FDA for treating people with myeloma who have had at least one prior therapy. Clinical trial results have shown a significant survival advantage for myeloma patients (who had received one to three prior therapies) treated with Revlimid®) plus dexamethasone versus dexamethasone alone.

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Immunotherapy
This is a treatment that uses immune cells or antibodies to fight the disease or suppress the progression of leukemia, lymphoma or myeloma and to enhance the specificity of treatment to minimize toxic effects on normal tissues. Three types of immunotherapy are being explored: antibody treatment, vaccine developmetn and immune cell administration.

Monoclonal antibodies are laboratory-produced proteins that can be infused into an appropriate patient. Some antibodies can be made to interact with a cell antigen and decrease the viability of the tumor cell, leading to its death. These antibodies are sometimes called "naked" antibodies, in contrast to antibodies carrying a radioactive agent or a toxin to kill the tumor cell.

Monoclonal antibodies have added to the arsenal of agents that can be used for the treatment of patients with lymphoma and leukemia. It is hoped that they can be added to chemotherapy without producing many toxic side effects.

Rituximab (Rituxan^®) is an antibody is directed at the target CD20 antigen on B-cell lymphoma cells. Cell surface antigens have been given a cluster designation (CD) followed by a number, thus rituximab is an anti-CD20 antibody. Rituximab has become an important agent to treat CD20-positive lymphocytic malignancies. Indeed, although initially used in indolent lymphomas,
such as follicular lymphoma, it has become an important fifth drug in the R-CHOP -- (rituximab cyclophosphamide, doxorubicin (Adriamycin®), vincristine (Oncovin®), and prednisone -- therapy of diffuse large B-cell lymphoma, the most prevalent lymphoma subtype.

Campath®-1H is a monoclonal antibody directed against the antigen CD52 found on T and B lymphocytes. It is especially active against the lymphocytes in CLL.

Another antibody that has been approved for use by the FDA to treat certain patients with acute myelogenous leukemia (AML) is linked to a chemical toxin called calicheamycin. This drug has the trade name Mylotarg^®. The drug is specifically for older patients who relapse after successful initial treatment.

Some monoclonal antibodies can be used to treat leukemia and lymphoma because they recognize and attach to specific cells. The monoclonal antibody can destroy the cancer cell when it attaches to the critical antigen on the cancer cell.

Monoclonal antibodies can also be linked to a radioactive isotope to target and kill specific cancer cells. These antibodies are injected into the patient in the hope that the antibodies will latch on to the antigen on the cancer cells and destroy the cells. These are called conjugated monoclonal antibodies. They deliver the toxic substance directly to the cancer cells. The drugs Zevalin® and Bexxar® are examples of this treatment. These drugs have been approved to treat relapsed B-cell non-Hodgkin lymphoma. 

In patients with CML who have relapsed after stem cell transplantation, the infusion of donor lymphocytes can reinduce remission. Patients with myeloma have also had remission re-induced by donor lymphocytes. This type of treatment is being studied intensively to learn more about the basis for this immune cell effect and to expand it for use in other situations.

Vaccines
Vaccines are now used to treat certain types of lymphoma. Studies of vaccines used in patients with follicular or indolent lymphoma demonstrated an immune response. Researchers are working on vaccines that could prevent cancer from recurring. The hope is that the immune system of the patient will inhibit the growth of cancer cells.

Many of the cancer vaccines under development are intended to induce antigen-specific anti-tumor immune responses. This means that the vaccine induces the immune response against the cancer cells present in the patient.

Vaccines have been developed and are in clinical trials for types of acute and chronic leukemia, lymphoma and myeloma. The goal is to extend the duration of
remission achieved by remission induction therapy of various types.

Some vaccines contain antigens or parts of antigens purified from cancer cells obtained from the patient or from the cancer cells of another patient. DNA vaccines are being tested that contain the DNA that encodes the specific antigen being tested. In some approaches, cells are isolated in the laboratory and start making antibodies after insertion of the cancer antigen. In each case, the basis for the vaccine is to make the cancer cells susceptible to immune attack by heightening the recognition of markers within cancer cells. The hope is that the immune system of the patient will inhibit the growth of cancer cells. Some vaccines are made from leukemic cells treated in test tubes to convert them to potent antigen-presenting cells.

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Reversal of Multidrug Resistance
The malignant cells of patients have mechanisms that may allow them to escape the damaging effects of chemotherapy agents. These cells are, or become, less responsive to therapy. Approaches to reversing multi-drug resistance are under study. The goal of several new agents being studied is to decrease resistance to an important chemotherapy drug used in leukemia. These agents are currently being tested in patients with AML and myeloma in the hope that they may decrease drug resistance and increase the rate of response to therapy.

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Gene Therapy
One approach is to use "antisense" agents that block the encoding instructions of an oncogene so that it cannot direct the formation of the corresponding oncoprotein that causes the cell to transform into a malignant cell. These agents can act on the gene (DNA) or on RNA to prevent the formation of the gene product or protein (oncoprotein) that is the direct cause of transforming the cell into a malignant type.

In another approach, drugs are designed to interfere with the oncoprotein and prevent its effect on the cell. In studies of CML, gene therapy researchers are trying to modify an oncogene (BCR-ABL) that produces a protein that stimulates malignant cell growth. An alternative strategy called molecular targeted drug development targets the oncoprotein. Two new and potentially important approaches include a) the application of RNA interference; b) a modality that uses molecules of RNA to silence complementary (DNA) genes; and aptamer treatment, a technique that prepares small molecules in the laboratory that have the ability to inactivate proteins that cause disease. If the gene in the former case is an oncogene or the protein in the latter case is an oncoprotein, new forms of cancer therapy may be developed.

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Blood and Marrow Stem Cell Transplantation

Allogeneic stem cell transplantation and autologous stem cell infusion are standard therapies for selected patients with certain subtypes of leukemia, lymphoma and myeloma. Advances in transplantation techniques, such as more precise HLA-matching, treating patients with immunosuppressive drugs, depletion of T lymphocytes from the donor graft, and using umbilical cord blood when appropriate as the source of donor cells, have helped to improve outcomes for transplant patients. A modified form of allogeneic transplant, nonmyeloablative or mini-transplant, is being studied to determine its usefulness in older patients or patients with less rapidly progressive blood cancers. Nonmyeloablative stem cell transplantations use less conditioning chemotherapy and radiation therapy than standard allogeneic transplant. Read more about stem cell transplantation.

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