IMMUNE SYSTEM ABLATION THERAPY FOR AUTOIMMUNE DISEASES

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Johns Hopkins Autoimmunity Day 2001  -  Notes by Dr.  Robert Brodsky


In the late 60s bone marrow transplant began to make its appearance in the medical practice, but a major block to its success was the need to suppress the patient's own immune system to the point where it would accept the bone marrow from other patients (allogeneic transplant).  To achieve this goal, George Santos, the founder of the Johns Hopkins bone marrow transplant program, introduced the use of high-dose cyclophosphamide (Cytoxan), a well-known drug used long term in low doses as immunosuppressant. 

Lyle Sensenbrenner, another Hopkins oncologist, noted that several of the patients Santos treated with high-dose cyclophosphamide were recovering their own bone marrow, instead of the donor's.  He then theorized that cyclophosphamide could be used to rebuild the bone marrow in patients with severe aplastic anemia (SAA) for whom all other therapeutic options had run out.

SAA is a lethal disease (about 80% mortality one year after the diagnosis) characterized by a >75% reduction in the cellularity of at least two of the three marrow blood cell lineages (erythroid, myeloid, and lymphoid), and mediated by an autoimmune attack of T lymphocytes against hematopoietic stem cells. 

Dr.  Sensenbrenner treated 10 young patients with SAA using the high-dose cyclophosphamide regimen, but then left Hopkins in 1987 and no one ever kept track of how his cyclophosphamide-treated patients fared long term --- until 1994 when Dr.  Robert Brodsky came along.  To his amazement, Dr.  Brodsky found that 7 of the 10 original SAA patients were not only alive but completely disease-free, with no relapse and no secondary disease.  He published these findings in Blood (87: 491-494, 1996), concluding the paper with a note of caution : "Although encouraging, these results remain preliminary.  The study was small and the patients were relatively young.  Hence, further studies with high-dose cyclophosphamide need to be performed".

Dr.  Brodsky then expanded the treatment to 20 additional patients with SAA using the following high dose cyclophosphamide protocol: 50 mg/Kg/day of cyclophosphamide for four days, followed by G-CSF to begin 6 days after the last cyclophosphamide dose.  The treatment was successful in 85% of the patients, thus confirming and expanding the original findings. 

It is now known how cyclophosphamide works, and why the bone marrow responds to this drug by bouncing back and recreating its own three blood cell lineages.  Cyclophosphamide is activated in the liver to phosphoramide mustard, which kills most of the actively replicating cells, such as the bone marrow cells.  Phosphoramide mustard is inactivated by the enzyme aldehyde dehydrogenase; thus, the cells that express this enzyme are resistant to phosphoramide attack. 

T and B lymphocytes, the cells that mediate the damage in autoimmune diseases, contain very little aldehyde dehydrogenase, and so are easily destroyed by cyclophosphamide.  Hematopoietic stem cells represent less than 1% of the bone marrow cells, and have the capacity to generate cells of all the three blood lineages.  Stem cells can be distinguished into two pools.  The low quality pool is made by large, lin+ and DR+ stem cells which do not express the enzyme aldehyde dehydrogenase; the high quality pool is made by small, lin-, DR- cells which express aldehyde dehydrogenase.  Thus, stem cells of the high quality pool are resistant to cyclophosphamide.  This means that patients receiving cyclophosphamide will have destroyed the existing mature blood cells, but will retain the ability to create new blood cells, avoid therefore the need for bone marrow transplant.  Simply put, cyclophosphamide ablates the bone marrow, but reboots its ability to form new hematopoietic cells, including new, nonautoimmune lymphocytes.

The high-dose cyclophosphamide treatment is effective, safe, represents 1/3 of the cost of a classical bone marrow transplant and avoid the reinfusion of the autoreactive lymphocytes that may contaminate the graft.  The treatment has a mild toxicity: complete alopecia (that begins about 2 weeks after the first dose), nausea and vomiting for the first 4-5 days, and lowering of the blood cell counts.  During this period, patients require transfusion of blood products (usually 1-2 units of red blood cells and 2-3 units of platelets), develop febrile neutropenia in about 70% of the cases, and may develop infections that require hospitalization .

With this background, the high-dose cyclophosphamide treatment is being tried in patients with other severe autoimmune diseases.  For example, it has been tried in 6 patients with pemphigus and in 13 patients with severe and unresponsive lupus erythematosus systemic.  All 6 patients with pemphigus have a good response, specifically 4 are in complete remission and 2 are in partial remission after the treatment.  Of the lupus patients, 6 are in complete remission, 3 in partial remission and 4 have no response.  In summary, high-dose cytoxan a) effectively ablates all the bone marrow cells, except the high quality stem cells, which are protected through the enzyme aldehyde dehydrogenase and can thus repopulate the marrow and "reboot" the immune system; b) cures severe aplastic anemia; c) can also cure other severe autoimmune diseases.