Ultra-Low Dose IL-2 Therapy as GVHD Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation

Although allogeneic stem cell transplantation (allo-SCT) is a curative option for many hematologic malignancies, not all have a suitable donor. Haploidentical peripheral blood stem cell transplantation (haplo-SCT) has the advantage of immediate availability, higher stem cell dose, and feasibility of repeated cell collections for generating lymphocyte infusions to treat or prevent relapse or infection. However, haplo-SCT incurs a risk of bidirectional rejection with either severe graft versus host disease (GVHD) or graft rejection by the recipient. Therefore it is important to develop novel strategies to optimize the outcome of haplo-SCT. Designing a haplo-SCT that incorporates the concepts of modulating the immune system and allowing the opportunity for graft manipulation and/or adoptive immunotherapy may improve the treatment outcome. To achieve this, we are first interested in studying the immune modulatory effect of ultra-low dose Interleukin 2 (ULD IL-2) as GVHD prophylaxis. This is an investigator initiated pilot study to determine the safety and feasibility of ULD IL-2 as GVHD prophylaxis in haploidentical allogeneic stem cell transplantation for patients with hematologic malignancies. Because GVHD has previously been associated with low numbers of circulating CD4+ CD25+FOXP3+ regulatory T cells (T(regs)), research efforts in increasing T(regs) either ex-vivo with adoptive transfer of T(regs) or in vivo using immunomodulatory agents such as IL-2, have shown promise in reducing incidences of GVHD. The primary objective of this study is to evaluate safety and feasibility. Secondary objectives are to determine the incidences of acute and chronic GVHD, engraftment, overall survival, transplant related mortality, and relapse. We will adopt the 2 step haplo-SCT method developed by Grosso et. al1 to study our method of GVHD prophylaxis. This 2 step approach, in which the lymphoid and myeloid portions of the graft are given in two separate steps in order to control and optimize T-cell, has already been published as a feasible and safe platform for haplo SCT for patients with hematologic malignancies and has been adopted by the Jefferson University Hospital (PA, USA), where they continue to treat patients under this protocol. As an additional GVHD prophylaxis, we will use sirolimus, an previously established GVHD prophylaxis which may work with ULD IL-2 synergistically to increase T(regs) . The haploidentical donor will be mobilized by G-CSF and undergo one apheresis to collect lymphocytes and CD34+ stem cell product after Miltenyi CD34+ selection. The products will be cryopreserved until the time of transplantation. Recipients will receive a myeloablative conditioning regimen of fludarabine and total body irradiation (TBI) on days -10 to -6. After the last fraction of TBI, a donor lymphocyte infusion (DLI) product (2 times 10(8) CD3+/kg) will be given. Cyclophosphamide will be given on days -3 and -2, followed by CD 34+ selected donor stem cell product infused on day 0. Sirolimus will be initiated on day -1 until day+60. ULD-IL2 (100,000 IU/m2) will give subcutaneously daily for 12 weeks starting day +1. This study will evaluate 14 recipients (ages greater than or equal to 18 - less than or equal to 75; planned accrual up to 20 recipient in event of replacement) with hematologic malignancies meeting indication for transplant but who do not have matched related or unrelated donor available. Safety will be monitored continuously with a stopping rule for toxicity based on the treatment-related serious adverse event rate (TRSAE). Safety monitoring will continue until at least 114 days after transplantation, and recipients experiencing adverse events will be monitored until toxicity resolution or stabilization. Stopping rule is defined as nonrelapse mortality and steroid refractory GVHD during the period of safety monitoring for ULD IL-2. Recipients will be followed for up to 1 year to evaluate the incidences of acute and chronic GVHD, engraftment, overall survival, transplant related mortality, and relapse.