RATIONALE: Giving a monoclonal antibody, such as alemtuzumab, and chemotherapy drugs, such as
fludarabine and melphalan, before a donor stem cell transplant helps stop the patient's
immune system from rejecting the donor's stem cells and helps stop the growth of abnormal
cells. When the healthy stem cells from a donor are infused into the patient they may help
the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.
Sometimes the transplanted cells from a donor can make an immune response against the body's
normal cells. Giving cyclosporine and mycophenolate mofetil before and after transplant may
stop this from happening.
PURPOSE: This phase II trial is studying how well giving alemtuzumab together with
fludarabine and melphalan followed by a donor stem cell transplant works in treating young
patients with resistant Langerhans cell histiocytosis.
- To determine the overall and disease-free survival of poor-risk pediatric patients with
Langerhans cell histiocytosis at 1 and 3 years after reduced-intensity hematopoietic
cell transplantation (RI-HCT).
- To determine day 100 transplantation-related mortality.
- To determine the incidence of hematopoietic recovery and chimerism at day 100 and at 1
year post RI-HCT.
- To determine the incidence of grades II-IV and III-IV acute graft-versus-host disease
- To determine the incidence of chronic GVHD.
OUTLINE: This is a multicenter study.
- Non-myeloablative conditioning: Patients receive alemtuzumab intravenously (IV) over 2
hours on days -8 to -4, fludarabine phosphate IV over 30-60 minutes on days -7 to -3,
and melphalan IV over 15-30 minutes on day -2. Some patients may receive anti-thymocyte
globulin IV on days -6 to -2 instead of alemtuzumab.
- Graft-versus-host disease prophylaxis and immunosuppression: Patients receive
cyclosporine A (CSA) IV or orally 2-3 times daily beginning on day -3 and continuing
until day 50 post transplantation, followed by a taper over 8 weeks in the absence of
GVHD or donor lymphocyte infusion given for decreasing donor chimerism. Patients with
mismatched donors (any source) and those receiving peripheral blood stem cells also
receive mycophenolate mofetil (MMF) IV or orally 2-3 times daily beginning on day -3 and
continuing to day 30 or 7 days after engraftment, whichever day is later, in the absence
of GVHD. In patients with acute GVHD requiring systemic therapy, Mycophenolate mofetil
(MMF) may be stopped 7 days after initiation of systemic therapy.
- Allogeneic hematopoietic stem cell infusion: Patients undergo infusion of bone marrow
(preferred) or peripheral blood stem cells on day 0. Patients also receive filgrastim
(G-CSF) subcutaneously or IV beginning on day 8 and continuing until blood counts
recover for 2 consecutive days.
- Donor lymphocyte infusion (DLI): Patients with mixed chimerism (i.e., < 95% donor) and
those with < 50% donor T-cell engraftment at any engraftment assessment time point are
eligible for DLI, in the absence of GVHD. If mixed chimerism persists, escalating doses
of CD3-positive lymphocytes are administered every 3-4 weeks, in the absence of GVHD.
After completion of study therapy, patients are followed from engraftment through day 100,
and then at 6 months, 1 year, and annually thereafter for 2-5 years.
- Histologically confirmed Langerhans cell histiocytosis (LCH) by demonstration of CD1a
positivity or Birbeck granules in lesions
- Considered poor-risk, defined as multisystem disease with involvement of one or more
risk organs (i.e., liver, spleen, lungs, and/or hematopoietic system)
- No isolated "lung only" LCH
- Progressive disease after one of the following treatments:
- LCH-III protocol or other standard LCH-directed therapies
- At least 1 course of the current salvage protocol (i.e., LCH-2 2005) or similar
therapy (e.g., cytosine arabinoside or cladribine-based regimens)
- HLA-matched related or unrelated donor OR unrelated umbilical cord blood (UCB)
- 1 locus mismatch for donor allowed
- Up to 2 loci mismatch for unrelated UCB allowed
- Any hematologic status (transfusion support allowed)
- Adequate hepatic, renal, cardiac, and pulmonary function to undergo reduced-intensity
hematopoietic cell transplantation (RI-HCT) including the following:
- Transaminases < 5 times upper limit of normal (ULN)
- Bilirubin < 3 times ULN (unless secondary to hepatic LCH)
- Creatinine ≤ 2 mg/dL (adults) (if creatinine > 1.2 OR history of renal
dysfunction, must have estimated creatinine clearance > 40 mL/min)
- Creatinine clearance > 40 mL/min (pediatrics)
- Glomerular filtration rate ≥ 50mL/min
- Negative pregnancy test
- Decompensated congestive heart failure, uncontrolled arrhythmia, or left ventricular
ejection fraction ≥ 35%
- Pulmonary failure (i.e., requiring mechanical ventilation) unless secondary to active
- Isolated liver sclerosis or pulmonary fibrosis unless secondary to active underlying
- Uncontrolled active life-threatening infection
- Pregnant or nursing
- Less than 4 weeks after last attempted salvage chemotherapy treatment
- Other concurrent chemotherapy agents (e.g., methotrexate) during entire
transplantation period up to day 100 post-transplantation