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Study Description

In people with MDS, the bone marrow stops making healthy blood cells and instead produces poorly functioning, malformed, and immature blood cells. This can lead to anemia resulting from too few healthy red blood cells, infection resulting from too few healthy white blood cells, and bleeding resulting from too few healthy platelets. The exact cause of MDS remains unknown, but it may be caused by abnormal autoimmune activity in which activated T cells, a type of white blood cell, prevent normal bone marrow production. ATG, a medication that inhibits immune function, can restore normal blood production in some people with MDS, but it is not known how this happens and why it does not happen in all MDS patients. The purpose of this study is to examine the effects of ATG in adults with MDS and to determine which individuals with MDS are most likely to benefit from treatment with ATG.

Based on disease severity and likely disease progression, participants will be separated into either a high-risk group or a low-risk group. Participants will be hospitalized for a 4-day period during which they will receive daily infusions of ATG. Oral prednisone will be given 2 days before hospitalization, throughout hospitalization, and then for 14 days after hospitalization to limit the side effects of ATG. Antihistamines and acetaminophen will also be given during hospitalization to reduce the chances of an allergic reaction to ATG. After discharge, all participants will attend monthly study visits that will include blood collection, review of disease symptoms, and evaluation of medication response. At Week 16, participants in the high-risk group will undergo additional blood collection, a bone marrow biopsy, and a thorough evaluation of disease progression and the effects of MDS on daily living abilities. Participants in the low-risk group will undergo these same procedures at Week 24. Follow-up for all participants may last up to 2 years.

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Study Inclusion/Exclusion Criteria

Inclusion Criteria:

  • Must understand and voluntarily sign an informed consent form
  • Age >=18 years at the time of signing the informed consent form
  • Must be able to adhere to the study visit schedule and other protocol requirements
  • Documented diagnosis of MDS that meets International Prognostic Scoring System (IPSS) criteria for Low - to Intermediate-1-risk disease (Group A) and Intermediate-2-risk disease (Group B)
  • Patients with Low and Int-1 IPSS will ONLY be eligible if they have clinically significant cytopenia with severe neutropenia (ANC < 1000), severe anemia (untransfused hemoglobin <9 g/dl), anemia requiring transfusion, OR thrombocytopenia (platelet count < 50,000/mm3)
  • Patients with Intermediate-2, same as above plus presence of 10% bone marrow blasts
  • Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

Exclusion Criteria:

  • Any serious medical illness that might limit survival to less than 2 years
  • Any other uncontrolled condition or illness. More information about this criterion can be found in the protocol
  • Prior anti-lymphocyte serotherapy (received serum from an immunized animal)
  • Proliferative (WBC <=12,000/µL) chronic myelomonocytic leukemia
  • MDS that is caused by radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases
  • Previous or concurrent malignancies except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast unless the subject has been free of disease for > 3 years
  • Receiving any other investigational agents
  • Any of the following abnormal lab values

                º Serum creatinine > 2.0 mg/dl or greater than institutional upper limit of normal (ULN)
                º Serum SGOT/AST or SGPT/ALT > 2.5 x ULN
                º Serum total bilirubin > 2.0 mg/dL (34 µmol/L)

  • History of a grade 2 National Cancer Institute common toxic criteria allergic reaction to rabbit proteins
  • Psychiatric illness that might limit the capacity of the subject from signing the informed consent form or might place the subject at unacceptable risk if he/she participates in the study due to non-compliance
  • HIV-1 positive
  • Uncontrolled concurrent illness including, but not limited to, acute viral illness, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnancy or breastfeeding

Study History

BACKGROUND

Study Disease (MDS)

MDS is a heterogeneous disease that is characterized by abnormal hematopoiesis that ranges from low-grade MDS to more aggressive stages that often progress to acute leukemia. Morbidity and mortality result from anemia, bleeding and infection. MDS is classified according to pathology by the French-American-British classification scheme-, which was slightly modified and adopted by the World Health Organization (WHO). The International Prognostic Scoring System (IPSS) separates patients into four distinctive prognostic subgroups. These IPSS subgroups include low-risk, intermediate-1, intermediate-2, and high-risk with median survival of 5.7, 2.6, 1.3, and 0.75 years, respectively. In addition, differences in outcome are associated with varied risk and time to AML progression, with a median duration to 25% AML conversion of 101 months in low-risk patients and as short as five months in high-risk patients. In this disease, cytogenetic and molecular abnormalities may alter hematopoiesis directly contributing to disease pathogenesis. Abnormal hematopoiesis is associated with reduced bone marrow differentiation, bone marrow stem cells with poor responsiveness to hematopoietic growth factors, over expression of inhibitory cytokines such as interferon-γ that lead to accelerated apoptosis, and abnormalities in bone marrow stem cell survival. There is evidence that an autoimmune mechanism mediates the bone marrow suppression associated with some forms of MDS. Several clinical trials have shown improvement in bone marrow development and long-term hematologic responses to immunosuppression.

Therapeutic Options in MDS

Management guidelines: Management decisions are primarily guided by survival estimations based on IPSS. For MDS patients, allogeneic stem cell transplantation remains the only curative treatment option, and is reserved for higher risk patients where procedure related mortality can be justified. Patients should be advised of the possibility of transplantation along with other options for treatment. However, most currently available treatment regimens may not alter survival, but instead focus on amelioration of cytopenias and infection in patients with lower risk disease with a concentrated effort toward improvement in quality of life. Therefore, the primary treatment for most lower-risk patients is supportive care.

Supportive Care: For patients with anemia, the options include transfusions, erythropoietin (EPO), and erythropoietin plus G-CSF for poor EPO responders. The overall probability of EPO response ranges from 17% to 30%. Antibacterial prophylaxis and colony stimulating factors (CSF) are available for patients with neutropenia. In patients with thrombocytopenia, thrombopoietic agents have been used with some limited effects in addition to platelet transfusions.

Induction chemotherapy: In patients with higher risk disease, AML induction chemotherapy has been used, especially in patients less than 60 years of age that are expected to better tolerate the treatment-related toxicities. However, response rates range from 15-51% and even if remission is achieved, it is difficult to maintain without transplantation.

DNA Methylation Inhibitors: A focus has been placed on the development of new therapeutic approaches for the treatment of MDS because of the increased incidence of the disease and the poor responses to available therapies. Newer approaches for the treatment of MDS focus on newly discovered molecular mechanisms of disease pathogenesis. The DNA methyltransferase inhibitor 5-azacitidine (AZA) is one such molecularly-targeted drug. This drug targets abnormalities in cytosine methylation that are important “epigenetic” modifiers of gene expression. Hypermethylation of DNA contributes to the malignant process in MDS. Two cytosine analogs, AZA and 5'-2-deoxycitidine (DAC) are currently available for “epigenetic” therapy. Clinical trials with 5-AZA were initiated two decades ago and revealed efficacy in AML and at lower doses in MDS. A Phase III randomized study comparing AZA to supportive care in treatment-naive MDS at various stages demonstrated response rates of 60% in the AZA arm (complete remission [CR] 7%, partial remission [PR] 16%, hematologic improvement [HI] 37%) compared to 5% in the supportive care arm (P < .001). These relatively durable responses (median 15 months) translated into an improved quality of life and a prolongation of median time to leukemic transformation or death from 13 months in the supportive care arm to 21 months in the AZA arm. Side effects were relatively modest, consisting primarily of myelosuppression. These results led to the recent US Food and Drug Administration (FDA) approval of AZA for the treatment of MDS. AZA is indicated for the treatment of all WHO subtypes.

DAC is more active than AZA in vitro and may have a different spectrum of activity and side effects compared to 5-AZA because it does not incorporate into RNA. Clinical trials with DAC were also initiated two decades ago and revealed promising efficacy in hematologic malignancies. Phase II studies of DAC in MDS revealed promising response rates of around 50% (CR rate around 20%), including cytogenetic responses, and minimal nonhematologic toxicity. These results led to a multi-institution Phase III study of DAC compared to supportive care in MDS. Data recently made public (but not subjected to peer review) suggested an improved time to AML or death in the DAC arm compared to the supportive care arm, particularly in treatment-naive patients (354 days vs. 189 days, p= .03) and high-risk MDS (260 days vs. 79 days, p= .001).

Antiangiogenesis Agents: Recognition that the malignant phenotype, which characterizes MDS, may arise from diverse biological processes has raised awareness that treatment strategies must be tailored to the specific pathophysiology observed in each individual patient. Novel therapies targeting chromatin structure, angiogenesis and the microenvironment that contribute to the MDS phenotype have demonstrated activity. Patient-select utilization of these therapies will likely result in enhanced responsiveness and alteration in the natural history of the disease.

An observation that increased microvessel density in the bone marrow led to the development of antiangiogenic agents for the treatment of MDS patients. Two antiangiogenic agents have been evaluated, which include Thalidomide and a more potent thalidomide analogue known as lenalidomide (CC5013). Unlike thalidomide with excessive risks of neurological toxicity, lenalidomide has been shown to be well tolerated and induce good response rates in preliminary studies. In the initial phase I/II clinical trial of 36 low-risk MDS patients, 24 (67%) experienced an erythroid response and 21 patients experienced sustained transfusion independence and a 2 g/dL rise in hemoglobin. A more extensive phase III trial of this agent is currently being conducted in a multi-institutional trial in the US.

Immune Suppression in MDS: Aberrant autoimmune activity is thought to induce ineffective hematopoiesis and bone marrow failure in some MDS patients. Identification of MDS patients with disease pathobiology related to aberrant autoimmunity will result in enhanced responsiveness to immunosuppressant therapy. Immunosuppressants are associated with durable clinical responses in 15-62% of patients with MDS. Table 2 summarizes the results of these clinical trials. Primarily, immunosuppressant therapies consist of combination of antilymphocyte or antithymocyte globulin (ALG and ATG) with and without cyclosporine and corticosteroids that eliminate bone marrow suppressive clonal T cells. In some patients with MDS, clonal amplification of T cells with restricted T cell receptor (TCR) Vβ chain genes provide evidence that clonal selection is under antigenic pressure. While the pathogenesis of the restricted Vβ repertoire is unknown, association of repertoire normalization after immunosuppression justifies further exploration of the relationship of this biological process to disease pathogenesis. Despite response rates of 15-62% in these reports, the appropriate use of immunosuppression in MDS patients remains highly controversial. One study performed by the Mayo Clinic was discontinued due to failure to respond in the first eight patients. If elimination of immunosuppressive clonal T cells is the mechanism of therapeutic responses, we hypothesize that the presence of T cell clones will provide positive predictive power for patients who are more likely to respond clinically to this form of therapy.

Careful delineation of patients predicted to respond and the mechanism of response to immune suppression are critical to improve the possibility of successful therapy. Treatment with immuneosuppression such as cyclosporine-A (CsA) or anti-thymocyte globulin (ATG, Thymoglobulin) yields frequent responses in selected MDS patients. In a previous report, one-third of MDS patients with less than 15% blasts developed red blood cell transfusion independence. Additionally, 87% of these responders have remained free of disease progression after 2.5 years. We hypothesize that activated lymphocytes mediate bone marrow suppression in patients that respond to Thymoglobulin. Therefore, the presence of clonal T cell populations may have predictive power for hematologic response to Thymoglobulin serotherapy. Furthermore, identifying the predictive power of the presence of T-cell clones for hematologic response to Thymoglobulin will potentially facilitate the appropriate selection of patients for this therapy in the future. This protocol has been designed to characterize the biologic role of activated lymphocytes and the mechanism of responses to Thymoglobulin through associated laboratory correlative studies. These studies are aimed at validating current concepts of the role, which subsets of immune cells play in the marrow failure state of this group of MDS patients and to study the predictive value of such tests in terms of clinical response to Thymoglobulin. Based on previous studies, we predict that at least 15-62% of patients are predicted to have a clinical response.

  • Study Activated March 29, 2007
  • First Accrual April 04, 2007
  • Study Closed on July 17, 2009

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