Clinical trial NCT00618540: Reduced Intensity Hematopoietic Cell Transplantation for Patients With Resistant Langerhans Cell Histiocytosis
Official title: Reduced Intensity Hematopoietic Cell Transplantation for Patients With Resistant Langerhans Cell Histiocytosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Histiocytosis, Langerhans-cell
Keywords: childhood Langerhans cell histiocytosis
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2008-02-20
Enrollment: 1
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: OBJECTIVES:

Primary

* 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).

Secondary

* 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 (GVHD).
* 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.

Eligibility criteria: Inclusion Criteria:

* 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) available

  * 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

Exclusion Criteria:

* Decompensated congestive heart failure, uncontrolled arrhythmia, or left ventricular ejection fraction ≥ 35%
* Pulmonary failure (i.e., requiring mechanical ventilation) unless secondary to active underlying LCH
* Isolated liver sclerosis or pulmonary fibrosis unless secondary to active underlying LCH
* 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

Primary outcomes:
measure: Overall Survival
timeFrame: Year 1, Year 3
measure: Disease-free Survival at 12 Months Post Transplantation
timeFrame: Year 1
Secondary outcomes:
measure: Transplantation-related Death
timeFrame: Day 100
measure: Neutrophil Engraftment
timeFrame: Day 100
measure: Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD)
timeFrame: Day 100 and Month 6
measure: Incidence of Chronic GVHD
timeFrame: Day 100 and Month 6
measure: Platelet Engraftment
timeFrame: Day 100
measure: Incidence of Grade III-IV Acute Graft-versus-host-disease (GVHD)
timeFrame: Day 100 and Month 6
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Angela Smith
role: PRINCIPAL_INVESTIGATOR
References: