A Randomized Trial of Recombinant Humanized Anti-IL-2 Receptor Antibody (Daclizumab) Versus Antithymocyte Globulin (ATG) to Treat the Cytopenia of Myelodysplastic Syndrome (MDS)
A Randomized Trial of Recombinant Humanized Anti-IL-2 Receptor Antibody (Daclizumab) Versus Antithymocyte Globulin (ATG) to Treat the Cytopenia of Myelodysplastic Syndrome (MDS)
This study will evaluate a new immunosupressive therapy, Daclizumab, and compare it with
 antithymocyte globulin (ATG) to treat cytopenia, that is, the deficiency of cellular elements
 of the blood, in myelodysplastic syndrome (MDS). Daclizumab is an anti-interleukin-2 receptor
 (IL-2) antibody. MDS, also known as myelodysplasia, is a disorder that can cause anemia,
 spontaneous bleeding, and greater risk of infections. Although the bone marrow can still
 produce some blood cells, very few reach the bloodstream. The cause of MDS is not known,
 although its behavior is. Many patients need transfusions of red blood cells. They may also
 develop leukemia, which is often quite resistant to treatment with chemotherapy. However, the
 progression of the disorder to leukemia is usually slow, taking many years.

 Patients 18 years of age and older who have MDS may be eligible for this study. Participants
 will undergo the following tests and procedures:

 -  Medical history and physical examination.

 -  Collection of blood for tests including blood counts, liver and kidney function, and
 antibodies against common viruses.

 -  Chest x-ray.

 -  Electrocardiogram.

 -  Bone marrow sample to confirm the diagnosis.

 Participants will randomly receive either ATG or Daclizumab. If they are in the group to
 receive ATG, they will be admitted as inpatients to undergo the first 10 to 14 days of
 treatment. If they do not already have a catheter in one of the large veins of the neck,
 chest, or arm, one will be placed. ATG will be given through the catheter. Blood counts and
 other blood analysis will be monitored daily while the patients are treated. After about 10
 days, they will be released, to be under the care of their referring physicians. Those
 participants who are in the group to receive Daclizumab will receive a total of five doses,
 one every 2 weeks, over 8 weeks, given through a vein as a 15-minute infusion. The first,
 third, and fifth dose will be given at the outpatient clinic. The second and fourth doses can
 be given either at the clinic or by the patients' primary hematologists.

 All patients will be followed as outpatients at 3-month intervals for the first year, and
 then every 6 months for the next 3 years. Afterward, follow-up will be yearly. A small sample
 of blood will be drawn at the visits. Also, bone marrow examinations will be requested at the
 6-month intervals for the first 3 years of treatment. If the treatment that patients are
 assigned to does not work, after 6 months, they will be eligible to receive the other
 treatment-provided that they have complied with the required blood tests and visits to the
 clinic required to assess the patients' safety.
Many bone marrow failure syndromes in humans are now recognized to result from immunological
 mechanisms. These diseases include aplastic anemia, pure red cell aplasia, and some types of
 myelodysplasia. Patients with these conditions, who may suffer variable degrees of anemia,
 leukocytopenia, and thrombocytopenia, alone or in combination, have been shown to respond to
 a wide variety of immunosuppressive agents, ranging from corticosteroids to cyclosporine
 (CSA) and antithymocyte globulin (ATG), however, nonresponse and relapse continues to be a
 problem. Why some patients do not respond initially or others respond and then relapse is
 unclear. Autoreactive T cells may be resistant to the effect of ATG/CsA (nonresponders),
 while in others residual autoreactive T cells expand post-treatment leading to hematopoietic
 stem cell destruction and recurrent pancytopenia (relapse). Therefore, novel, less toxic
 immunosuppressive regimens that increase response rates and hematologic recovery and decrease
 relapse rates are needed.

 One such novel therapy, Daclizumab, a humanized anti-interleukin-2 receptor (lL-2R)
 monoclonal antibody (mAb), acts against activated lymphocytes, thus sharing an important
 mechanism of action with ATG. The mAb is much less toxic than ATG and may be administered to
 outpatients at relatively infrequent intervals (every 2 weeks). Treatments with ATG alone and
 CsA alone have demonstrated varying degrees of success in alleviating the cytopenia of MDS.
 Our experience suggests that ATG rather than CSA is the more effective agent inducing
 hematological responses in susceptible MDS patients and that certain variables including the
 patient's age, whether or not they were HLA DR15, and days of red cell transfusion dependence
 prior to treatment were predictive of response.

 We therefore propose this randomized phase II study to evaluate and compare a new
 immunosuppressive therapy, Daclizumab, with antithymocyte globulin (ATG) to treat the
 cytopenia of MDS in a population of subjects with intermediate or high predicted probability
 of response.
INCLUSION CRITERIA:

 MDS of RA, RARS & RAEB sub-types including those previously treated with chemotherapy or
 experimental agents such as retinoids, Vitamin D, and growth factors

 Anemia requiring transfusion support with at least one unit of packed red blood cells per
 month for greater than or equal to 2 months

 OR

 thrombocytopenia (platelet count less than 50000/ul)

 OR

 neutropenia (absolute neutrophil count less than 500/ul).

 Off all other treatments (except G-CSF, and transfusion support and related medications)
 for at least four weeks. G-CSF can be used before, during and after the protocol treatment
 for patients with documented neutropenia (less than 500/Ul) as long as they meet the
 criteria for anemia and/or thrombocytopenia as stated above.

 ECOG performance status less than or equal to 2

 High or intermediate predicted probability of response

 EXCLUSION CRITERIA:

 MDS of FAB sub-group chronic myelomonocytic leukemia (CMML)

 Transformation to acute leukemia (FAB sub-group RAEB-T, ie, greater than 20% blasts in
 marrow aspirate)

 Hypoplastic marrow without one major or two minor criteria

 Treatment with growth factors (except for G-CSF) or cyclosporine within 4 weeks prior to
 entry to protocol

 Recent or current treatment (24 hours wash out period) with the herbal supplement Echinacea
 purpurea or Usnea barbata (Old Man's Beard)

 ECOG performance status of greater than 2

 Active uncontrolled infection (chronic or current clinically significant infection,
 including hepatitis B or C virus infection)

 Current pregnancy, or unwilling to take oral contraceptives or refrain from pregnancy if of
 childbearing potential

 Patients for whom bone marrow transplant is indicated as standard therapy (age less than
 fifty-five with a fully-matched sibling donor)

 Age less than 18 years

 Not able to understand the investigational nature of the study or give informed consent

 HIV positive patients

 Active malignant disease (excluding basal cell carcinoma)

 Serum creatinine greater than 2mg/dl

 Patients who are moribund or patients with concurrent hepatic, renal, cardiac, metabolic,
 or any disease of such severity that death within 3 months is likely

 Low predicted probability of response