CHP-753, Rapamycin for Immunosuppression and B Cell Modulation Post Stem Cell Transplant for Acute Lymphoblastic Leukemia (ALL)
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
Rapamycin studies in conjunction with a calcineurin inhibitor (CSA or FK506) At the Dana
Farber Cancer Institute (DFCI), 50 patients with related, human leukocyte antigen (HLA)
matched peripheral stem cell transplants were studied using the combination of FK506 and
repaying. The hypothesis tested was that the omission of methotrexate would not increase the
rate of GVHD, and would reduce toxicity. The rate of grade II-IV acute GVHD was 16%, and
III-IV 5%, which is extremely favorable for adults. Transplant related mortality at 100 days
This study was done following an earlier study of low dose methotrexate in the higher risk
unrelated donor transplant patient. This study showed that rapamycin provided excellent
GVHD prevention in the high-risk cohort.
We will substitute FK506 for cyclosporine as per the Boston experience. This will be
considered a standard practice within our division to increase patient compliance and
comfort. This does not increase risk to patients, as oral FK506 is better tolerated RAPA
and FK506 appear to be synergistic which may result in better GVHD prophylaxis.
1. Thiotepa 5 mg/kg days -7, -6. Given IV over 4 hours. Cyclophosphamide 60 mg/kg days -5,
-4. Given over 1 hour IV with routine supportive care.
2. Total body irradiation (TBI) 200 cGy/fraction x 6 fractions given over 3 days*.
Testicular boost 400 cGy may be given for males. Patients with prior CNS disease and no
prior central nervous system (CNS) irradiation: 600 cGy prior to starting conditioning.
*TBI may be given before or after Thiotepa and cyclophosphamide. If given before Stem
cells are to be given 48 hours after the end of cyclosphosphamide.
Graft vs. Host Disease Prophylaxis:
1. Tacrolimus IV by continuous infusion .03mg/kg per day beginning day -3. Target serum
levels between 5-10 patients will switch to oral form when tolerating PO's ("Per Os" or
2. Methotrexate 5mg/m2 will be given IV on days 1, 3, and 6 for all patients and on day 11
for patients receiving unrelated donor marrow.
3. Rapamycin day 0 with dosing as follows: 2.5 mg/m2/d (4mg/d max) PO daily.
Absent GVHD Immune Suppression Weaning:
1. Tacrolimus: Matched sibling donor allograft taper at day +42 over 6-8wks. Mismatched
or unrelated allograft or cord blood taper at day +100 to be off by day +180.
2. Sirolimus: At day + 180 wean over 4 weeks.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants With Transplant-related Mortality
Death not associated with relapse. We determined that if transplant related mortality(TRM) 25% at day 100 or if Grade III-IV (severe, life threatening, or disabling) acute GVHD was >30% a stopping rule would be triggered.
24 months after transplant
Michael Pulsipher, MD
Primary Children's Medical Center
United States: Institutional Review Board
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