Medical Technology

How Doctors are Fighting Drug Resistant Leukemia



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As with many other forms of cancer, a major obstacle to successful treatment of leukemia is the emergence of cancer cells resistant to first line chemotherapy agents. In other words, the drugs used in the initial round of chemotherapy may fail to induce remission altogether, or drug resistant cancer cells reappear after an interval of months to years. In both scenarios, treatment options are limited but fall into three general categories: a) alternative chemotherapy agents to which the patient has not been exposed b) a trial of immunotherapy or c) a bone marrow or stem cell transplant as a treatment of last resort.  

Alternative chemotherapy agents

Since the approval of imatinib (Gleevec) for the treatment of CML (chronic myelogenous leukemia) a decade ago, tyrosine kinase inhibitors have come into widespread use as a treatment for other forms of leukemia as well as certain other cancers in both the initial and recurrent phases. The rationale behind tyrosine kinase inhibitors is that they block growth promoting signals from a variety of sources. These include overexpressed growth factor receptors on the cell membrane, src family tyrosine kinases in the cytosol, and the abnormal bcr-abl protein that drives proliferation of leukemia cells in CML and 30% of cases of ALL (acute lymphoblastic leukemia). Because tyrosine kinase inhibitors bind to multiple target proteins, chances are the tumor cells will maintain some degree of susceptibility to them even as they become resistant to other chemotherapy agents.

Immunotherapy

Briefly, immunotherapy involves extracting a patient's lymphocytes (assuming healthy ones can be found), exposing them to tumor antigens, then injecting these primed lymphocytes back into the patient. The hope is that following this special round of training, the lymphocytes will destroy as many tumor cells as possible. This strategy has shown promise with melanoma; whether it works effectively in leukemia patients remains to be seen.

A second promising strategy is the development of monoclonal antibodies to selectively target tumor cells. One example is Rituximab (Rituxan), first used in the treatment of CD20 positive Non-Hodgkin's Lymphoma (NHL). Although NHL differs in some respects from leukemia, both forms of cancer tend to arise as tumors of B cell origin. As of 2010, Rituxan was approved for use in treating CLL (Chronic Lymphoblastic Leukemia).

Bone marrow and Stem Cell Transplants

Bone marrow transplants (BMT) are sometimes successful in treating recurrent leukemias. The strategy is to extract bone marrow from a genetically compatible donor, subject the patient to total body irradiation (hopefully eradicating all tumor cells in the process), and then use this marrow (which contains the stem cell progenitors of every kind of blood cell) to reconstitute the patient's immune system with healthy cells. The acute risks are that the transplanted cells will not take up residence in the patient's marrow or fail to produce enough functional blood cells to reconstitute the patient's immune system. In either case, the invariable outcome is death from opportunistic infections. A long term complication of BMT is a phenomenon called Graft Versus Host Disease (GVHD), described below.

In recent years, stem cell transplants have superseded BMT at various tertiary care centers across the U.S. The overall procedure remains the same; however, the advantage of using purified hematopoietic stem cells over bone marrow is a much lower risk of GVHD. This disorder results from the introduction of donor lymphocytes (or their precursors) that regard the recipient's entire body as foreign tissue (as opposed to self). Weeks or even months after the transplant, these autoreactive lymphocytes attack the skin, liver, and/or gastrointestinal tract. GVHD is potentially fatal; hence, oncologists tend to prefer stem cell transplants over BMT in the treatment of leukemia.

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