Low Dose IL-2, Hematopoietic Stem Cell Transplantation, IL2 for GVHD (IL2 for GVHD)

Phase II Trial Using Low Dose IL-2 to Induce Regulatory T Cells in Patients After Allogeneic Hematopoietic Stem Cell Transplantation as Graft Versus Host Disease Prophylaxis

The Methodist Hospital Research Institute, Center for Cell and Gene Therapy, Baylor College of Medicine

Patients are being asked to participate in this study because treatment for their disease requires a stem cell transplant (SCT). Stem cells are the source of normal blood cells found in the bone marrow and lead to recovery of blood counts after bone marrow transplantation. With stem cell transplants, regardless of whether the donor is a full match to the patient or not, there is a risk of developing graft-versus-host disease (GVHD). GVHD is a serious and sometimes fatal side effect of SCT. GVHD occurs when the new donor stem cells (graft) recognizes that the body tissues of the patient (host) are different from those of the donor. When this happens, cells in the graft may attack the host organs. How much this happens and how severe the GVHD is depends on many things, including how different the donors cells are, the strength of the drugs given in preparation for the transplant, the quality of transplanted cells and the age of the person receiving the transplant. Typically, acute GVHD occurs in the first 100 days following transplant, while chronic GVHD occurs after day 100. Acute GVHD most often involves the skin, where it can cause anywhere from a mild rash to complete removal of skin; liver, where it can anywhere from a rise in liver function tests to liver failure; and the gut, where it can cause anywhere from mild diarrhea to profuse, life-threatening diarrhea. Most patients who develop GVHD experience a mild to moderate form, but some patients develop the severe, life-threatening form. Previous studies have shown that patients who receive SCT's can have a lower number of special T cells in their blood, called regulatory T cells, than people who have not received stem cell transplants. When regulatory T cells are low, there appears to be an increased rate of severe, acute GVHD. A drug known as IL-2 (Proleukin) has been shown to increase the number of regulatory T cells in patients following stem cell transplant, and in this study investigators plan to give low dose IL-2 after transplant. This study is called a phase II study because its major purpose is to find out whether using a low-dose of IL-2 will be effective in preventing acute GVHD. Other important purposes are to find out if this treatment helps the patient's immune system recover regulatory T cells faster after the transplant. This study will assess the safety and toxicity of low-dose IL-2 given to patients after transplantation and determine whether this drug is helpful in preventing GVHD.

Participation in this protocol will last about 1 year. To participate in this study, the patient will need to have undergone a stem cell transplant. Before the treatment starts, investigators would like to test the patient's blood blood for the number of regulatory T cells already present before beginning IL-2. Treatment Plan: Before the conditioning treatment for the transplant, 30 to 40 ml (6 to 8 teaspoonfuls) of blood will be collected from the patient for regulatory T cell analysis. Approximately same amount of blood will also be collected on day 0 (the day of the transplant), and at the following times after the transplant: day 7 (the day the IL-2 will most likely start) then weekly for another eleven weeks, then monthly for 8 months. On approximately day 7 following the transplant, if the patient is well and meets the eligibility requirements, the IL-2 injections will begin. These will be given subcutaneously (as a small injection just under the skin) three times per week for 6 weeks. The injections may also been given through a special catheter, called an Insuflon catheter, that is placed just under the skin for a week at a time. The first dose must be given in the hospital, but the remaining doses can be given at home. The patient will be taught how to give the injections to him/ herself. If the patient's body has no serious toxicities from the IL-2 and has not developed severe GVHD, the patient can continue to get the injections the same way for an additional 6 weeks. If at any time the patient develops severe GVHD or serious toxicity related to the IL-2,the injections will be stopped. If the patient's disease returns (relapse) or he or she does not engraft (accept the donor graft), the patient will be removed from the study. The patient's labs will be followed closely while he/she is receiving the IL-2 injections, as well as heart, kidney and lung functions; however, these are all standard tests that the patient will receive after transplant regardless of participation in this study.

Acute Lymphoblastic Leukemia, ALL, Acute Myelogenous Leukemia, AML, Chronic Myelogenous Leukemia, Myelodysplastic Syndrome, Myeloproliferative Disorder, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Non-malignant Diseases Requiring Allogeneic HSCT

Stem Cell transplant, Graft verus host disease, IL-2, acute lymphoblastic leukemia, ALL, acute myelogenous leukemia, AML, chronic myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, Hodgkin lymphoma, non-Hodgkin lymphoma, non-malignant diseases requiring allogeneic HSCT

SCHEDULE OF IL-2 ADMINISTRATION: Patients will receive a fixed dose (1x10e5 units/m2/dose) of IL-2 given as a subcutaneous injection three times weekly (separated by at least one day) for 6 weeks beginning no earlier than day +7 after HSCT but beginning no later than 30 days after HSCT. Time will be measured as 'week beginning with first IL-2 injection.' T cell Induction via IL-2 to reduce GVHD

IL2 Administration: Patients will be given a fixed dose (1x10e5 units/m2/dose) of IL-2 given as a subcutaneous injection three times weekly (separated by at least one day) for 6 weeks beginning no earlier than day +7 after HSCT but beginning no later than 30 days after HSCT. If the patient has not developed >grade I side effects to IL-2 and has not developed >grade I GVHD then the patient may continue the IL-2 for 6 additional weeks. Time will be measured as 'week beginning with first IL-2 injection.

Assessment of the safety and the toxicity of low-dose IL-2, administered according to the dosage described in this protocol, in this group of patients The outcome measure is the proportion of participants with dose limiting toxicities.

To investigate the immunomodulatory effects of IL-2 administered after allogeneic hematopoietic stem cell transplantation

To conduct ancillary studies on those patients to investigate before, during and after IL-2 administration to determine: The immunophenotype of PBMCs The suppressive activity of CD4+ CD25+ FoxP3+ Tregs Cytokines secreted by PBMCs NK cell analysis

INCLUSION CRITERIA: INCLUSION CRITERIA FOR INITIAL STUDY ENROLLMENT: Patients will be eligible for initial enrollment on this study as long as they meet the following criteria: Diagnosis of acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, Hodgkin lymphoma, non-Hodgkin lymphoma or non-malignant disease requiring allogeneic HSCT Birth to age 70 years of age Study entry consent is signed and faxed to Research Coordinator INCLUSION CRITERIA AT TIME OF IL-2 ADMINISTRATION: At least day +7 post transplant Less than or equal to 30 days post transplant Lansky or Karnofsky score greater than or equal to 50% Total bilirubin less than or equal to 1.5mg/dL Alanine aminotransferase level (ALT) less than or equal to five times normal, serum direct bilirubin less than or equal to 1.5mg/dL, albumin greater than or equal to 3.0gm/dL Serum creatinine less than three times normal or creatinine clearance greater than 80mg/min/1.73m2 Ensure that informed consent signed and faxed to Research Coordinator EXCLUSION CRITERIA: EXCLUSION CRITERIA AT TIME OF IL-2 ADMINISTRATION: Patients will be ineligible to receive IL-2 injections if any of the following is true: Active, acute GVHD greater than or equal to grade II Serious, active bacterial, fungal or viral infection (i.e. intensive care) Clinical Signs of severe pulmonary dysfunction Clinical Signs of sever cardiac dysfunction Receiving corticosteroids as GVHD treatment Hypersensitivity or allergy to IL-2

Kennedy-Nasser AA, Ku S, Castillo-Caro P, Hazrat Y, Wu MF, Liu H, Melenhorst J, Barrett AJ, Ito S, Foster A, Savoldo B, Yvon E, Carrum G, Ramos CA, Krance RA, Leung K, Heslop HE, Brenner MK, Bollard CM. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin Cancer Res. 2014 Apr 15;20(8):2215-25. doi: 10.1158/1078-0432.CCR-13-3205. Epub 2014 Feb 26.