CHP-753, Rapamycin for Immunosuppression and B Cell Modulation Post Stem Cell Transplant for Acute Lymphoblastic Leukemia (ALL)

Objectives:

Primary objective: Evaluate toxicity of rapamycin when used for post-bone marrow transplant graft vs. host disease prophylaxis in children with acute lymphoblastic leukemia (ALL).

Rapamycin Rapamycin (RAPA, RapamuneR) (sirolimus) is an immunosuppressive agent that was approved by the FDA in 1999. It is a macrocyclic lactone that is structurally similar to Tacrolimus (FK506) and binds to the same intracellular protein as FK506, FKBP1,2,3, but it has an entirely different mechanism of action and a different principal target protein. The target of the RAPA: FKBP complex is the mammalian target of rapamycin (mTOR). Unlike the calcineurin inhibitors cyclosporine (CSA) and - FK506, RAPA exerts its effects by inhibiting growth factor-driven transduction signals in the T-cell response to alloantigen, thus preventing proliferation among T and B lymphocytes3,4. This action is at a later stage in T cell mediated response than that of CSA or FK506. Important cyclin-dependent signaling kinases are blocked, which results in cell cycle arrest between G1 and S phase. RAPA prevents factor dependent growth of activated T cells, but does not prevent the autocrine production or release of growth factors from activated T cells. Rapamycin has been studied in clinical trials of solid organ allografts, and have been shown to prolong allograft survival by inhibiting host CD4+ and CD8+ T cell expansion5, 6. RAPA has synergistic immunosuppressive properties when used with CSA or FK506, and its use allows lower doses of the more nephrotoxic calcineurin inhibitors to accomplish decreased rejection. The use of full dose calcineurin inhibitors with RAPA can result in nephrotoxicity, but these agents can be safely used at a reduced dose with RAPA.

Our goal with Rapamycin is to achieve two necessary ends with one medication: a leukemic precursor effect (see above), and prevention of graft vs. host disease (GVHD). With CSA OR FK506, acute GVHD develops in approximately 40% of pediatric matched related donor recipients, and the majority is mild and easily controllable by the addition of methylprednisolone or prednisone. At Children's hospital of Philadelphia (CHOP), "short course" methotrexate in addition to CSA OR FK506 is given only to patients >14 years, or those with older donors. Chronic GVHD occurs in approximately 20% of pediatric matched related donor recipients, and 75% of this is limited to skin. Therefore, the use of RAPA in this group may accomplish adequate immunosuppression so as to prevent GVHD, as well as provide anti- B and anti-T cell malignancy effect. RAPA may also prove less toxic than the calcineurin inhibitors as well, in which both nephrotoxicity and neurotoxicity remain serious side effects.

Allogeneic bone marrow transplantation for children with ALL Children who have very high-risk features, such as t(4;11) or t(9;22), or those who relapse while on chemotherapy are rarely cured by chemotherapy alone. These patients, as well as those beyond second remission, are generally referred for allogeneic stem cell transplantation. Approximately 25-30% of these patients will have a matched sibling donor. Matched sibling, matched unrelated, and cord blood donor bone marrow transplant results in approximately 40-60% of patients surviving disease free, but relapse remains the largest obstacle to cure. Rapamycin, with its apoptotic effects upon B cell precursor malignancies, may prove effective in decreasing the incidence of relapse in these patients, particularly when used in a state of minimal residual disease post transplant. We expect to treat approximately 10 patients with ALL yearly with matched related donor BMT between the four centers involved in this study.