Histiocytosis, Langerhans-cell
Conditions
Keywords
childhood Langerhans cell histiocytosis
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.
Interventions
BIOLOGICALalemtuzumab
Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4.
DRUGfludarabine phosphate
Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age \<12 months)
DRUGmelphalan
Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age \<12 months)
PROCEDUREstem cell transplantation
Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Year 1, Year 3 | Count of patients alive at 1 and 3 years. Deaths from any cause are events. Surviving patients are censored at the date of last contact. |
| Disease-free Survival at 12 Months Post Transplantation | Year 1 | This outcome is defined as survival with resolution of LCH at 12 months post transplant. Unresolved disease for over 12 months post-transplant, progressive disease after this time period, recurrence of disease and death from any cause are considered events. Those who survive with resolution of disease are censored at the date of last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD) | Day 100 and Month 6 | The occurrence of skin, gastrointestinal or liver abnormalities fulfilling the criteria of Grades II, III and/or IV acute GVHD are considered events (Appendix II). Patients without acute GvHD will be censored at the time of death or last follow-up. Patients that survive \<21 days and listed as not evaluable will be excluded. Patients receiving a second transplant will be censored at the time of second transplant. |
| Incidence of Chronic GVHD | Day 100 and Month 6 | Occurrence of symptoms in any organ system fulfilling the criteria of limited or extensive chronic GvHD (Appendix III), among patients surviving \> 90 days with evidence of engraftment. Patients without chronic GvHD will be censored at time of death or last follow-up. |
| Transplantation-related Death | Day 100 | Count of patients who died by day 100 related to the transplantation. |
| Incidence of Grade III-IV Acute Graft-versus-host-disease (GVHD) | Day 100 and Month 6 | The occurrence of skin, gastrointestinal or liver abnormalities fulfilling the criteria of Grades II, III and/or IV acute GVHD are considered events (Appendix II). Patients without acute GvHD will be censored at the time of death or last follow-up. Patients that survive \<21 days and listed as not evaluable will be excluded. Patients receiving a second transplant will be censored at the time of second transplant. |
| Platelet Engraftment | Day 100 | Incidence of platelet recovery and donor chimerism at Day 100. |
| Neutrophil Engraftment | Day 100 | Incidence of neutrophil recovery and donor chimerism at Day 100. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alemtuzumab Conditioning Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis.
alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4.
fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3.
(dose adjust if age \<12 months)
melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age \<12 months)
stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Alemtuzumab Conditioning |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 1 / 1 |
Outcome results
Primary
Disease-free Survival at 12 Months Post Transplantation
This outcome is defined as survival with resolution of LCH at 12 months post transplant. Unresolved disease for over 12 months post-transplant, progressive disease after this time period, recurrence of disease and death from any cause are considered events. Those who survive with resolution of disease are censored at the date of last contact.
Time frame: Year 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab Conditioning | Disease-free Survival at 12 Months Post Transplantation | 0 participants |
Primary
Overall Survival
Count of patients alive at 1 and 3 years. Deaths from any cause are events. Surviving patients are censored at the date of last contact.
Time frame: Year 1, Year 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab Conditioning | Overall Survival | 0 participants |
Secondary
Incidence of Chronic GVHD
Occurrence of symptoms in any organ system fulfilling the criteria of limited or extensive chronic GvHD (Appendix III), among patients surviving \> 90 days with evidence of engraftment. Patients without chronic GvHD will be censored at time of death or last follow-up.
Time frame: Day 100 and Month 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab Conditioning | Incidence of Chronic GVHD | 0 participants |
Secondary
Incidence of Grade III-IV Acute Graft-versus-host-disease (GVHD)
The occurrence of skin, gastrointestinal or liver abnormalities fulfilling the criteria of Grades II, III and/or IV acute GVHD are considered events (Appendix II). Patients without acute GvHD will be censored at the time of death or last follow-up. Patients that survive \<21 days and listed as not evaluable will be excluded. Patients receiving a second transplant will be censored at the time of second transplant.
Time frame: Day 100 and Month 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab Conditioning | Incidence of Grade III-IV Acute Graft-versus-host-disease (GVHD) | 0 participants |
Secondary
Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD)
The occurrence of skin, gastrointestinal or liver abnormalities fulfilling the criteria of Grades II, III and/or IV acute GVHD are considered events (Appendix II). Patients without acute GvHD will be censored at the time of death or last follow-up. Patients that survive \<21 days and listed as not evaluable will be excluded. Patients receiving a second transplant will be censored at the time of second transplant.
Time frame: Day 100 and Month 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab Conditioning | Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD) | 1 participants |
Secondary
Neutrophil Engraftment
Incidence of neutrophil recovery and donor chimerism at Day 100.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab Conditioning | Neutrophil Engraftment | 1 participants |
Secondary
Platelet Engraftment
Incidence of platelet recovery and donor chimerism at Day 100.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab Conditioning | Platelet Engraftment | 0 participants |
Secondary
Transplantation-related Death
Count of patients who died by day 100 related to the transplantation.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab Conditioning | Transplantation-related Death | 0 participants |