Hemophagocytic Lymphohistiocytosis
Conditions
Keywords
hemophagocytic lymphohistiocytosis, hybrid immunotherapy, dexamethasone, Etoposide, ATG,rabbit
Brief summary
Despite good progress during the last decade, hemophagocytic lymphohistiocytosis (HLH) remains difficult to treat. Two different treatment regimens have been used successfully. The first one, a treatment regimen based on two drugs called etoposide and dexamethasone, has been used worldwide. The second regimen, based on two drugs called Anti-thymocyte globulin (ATG) and prednisone, has been used mostly at one hospital in Paris, for over 15 years. With either regimen, about three quarters of treated children survive the most difficult time, the first two months after diagnosis. These two different regimens appear to work somewhat differently, and we suspect that combining them may give better results than either regimen alone. We are conducting this clinical trial to test the combination of ATG, dexamethasone, and etoposide for the treatment of HLH. The purpose of this research study is to find out what effects (good and bad) this drug combination has on you and your HLH.
Detailed description
Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder first recognized almost 70 years ago.(1) Genetic and animal studies have indicated that the familial form of HLH is clearly due to a deficiency of cytotoxic killing. Patients with HLH present with a potentially fatal syndrome of 'hyperimmunity.' These patients have severe inflammation, associated with cytopenias and variably severe bone marrow, liver, or CNS damage. Tissue damage and mortality appear to be due to hypercytokinemia related to persistent immune hyperactivation. An animal model of HLH and correlative human studies all suggest that excessive and abnormal activation of T cells drives the pathophysiology of this disorder, and that suppressing this excessive activation is critical for successful therapy of HLH. It is believed a combination of the two proven induction regimens for hemophagocytic lymphohistiocytosis (HLH) (anti-thymocyte globulin (ATG)- and etoposide-based) will result in response rates and overall survival rates at eight weeks which are comparable or better than the current standard of care (induction therapy per the HLH-94 protocol).
Interventions
DRUGATG, rabbit
ATG, rabbit (Thymoglobulin, Genzyme) will be dosed at 5 mg/kg/dose, given IV on 5 consecutive days (titrated over 4 to 8 hours).
DRUGEtoposide
Etoposide will be dosed at 150mg/m2, given IV. The first dose will be given 7 days (+/- 2 days) after the first dose of ATG, and be given weekly for a total of 7 doses.
DRUGMethotrexate
Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients (CNS+ patients are those patients which have any of the following: elevated CSF (cerebral spinal fluid) protein or white count, seizures, focal or global neurologic deficit, MRI abnormalities consistent with CNS involvement by HLH.) in the following doses: age\< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, \>3 yrs: 12/15 mg. It will be administered (+/- 3 days) on day 7, 14, 21 and 42.
DRUGhydrocortisone
Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients (CNS+ patients are those patients which have any of the following: elevated CSF (cerebral spinal fluid) protein or white count, seizures, focal or global neurologic deficit, MRI abnormalities consistent with CNS involvement by HLH.) in the following doses: age\< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, \>3 yrs: 12/15 mg. It will be administered (+/- 3 days) on day 7, 14, 21 and 42.
DRUGDexamethasone
will be started with the ATG. It will be divided BID, given IV for at least 1 week before switching to PO. Dosing: 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days.
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
* diagnosis of hemophagocytic lymphohistiocytosis * Patients \<18 years of age * The patient must have active disease at the time of enrollment * Patient's legal guardians must sign an Institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study. * Eligible subjects must be enrolled with the protocol coordinating center
Exclusion criteria
* Recent treatment, within 3 months, with another therapeutic regimen for HLH * Known active malignancy * Known rheumatologic diagnosis which may be the underlying cause of HLH * Pregnancy (as determined by serum or urine test) or active breast feeding * Failure to provide signed informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 8 Weeks | To determine the overall survival of patients with hemophagocytic lymphohistiocytosis at 8 weeks after an ATG/etoposide-based induction regimen and to determine the feasibility of this approach in the context of a multicenter clinical trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Response | 8 Weeks | To determine the median time to complete response during 8 weeks of therapy |
| Overall Survival | up to day 180 | To determine overall survival prior to the initiation of BMT (bone marrow transplant) preparative regimen (or day 180, if BMT preparative regimen not yet begun) |
| Number of Participants Who Experienced Reactivation | up to 180 days | To determine the frequency of disease reactivation prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun) |
| Overall Survival to Day +100 | up to day 280 | To determine overall survival to day +100 after BMT, for patients who have undergone BMT within 6 months of study entry |
| Disease Status at BMT | up to day 180 | To determine the rate of complete response at the time of BMT preparative regimen initiation |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Induction Therapy ATG, rabbit: intravenous, 5 mg/kg/dose, 5 consecutive days Dexamethasone: intravenous, 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days Etoposide: intravenous, 150 mg/m2 weekly, starting 7 days after first dose of Thymoglobulin Methotrexate and hydrocortisone: intrathecal to patients with central nervous system involvement, age\< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, \>3 yrs: 12/15 mg, on day 7, 14, 21 and 42
ATG, rabbit: ATG, rabbit (Thymoglobulin, Genzyme) will be dosed at 5 mg/kg/dose, given IV on 5 consecutive days (titrated over 4 to 8 hours).
Etoposide: Etoposide will be dosed at 150mg/m2, given IV. The first dose will be given 7 days (+/- 2 days) after the first dose of ATG, and be given weekly for a total of 7 doses.
Methotrexate: Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients | 31 |
| Total | 31 |
Baseline characteristics
| Characteristic | Induction Therapy |
|---|---|
| Age, Categorical <=18 years | 31 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 31 |
| other Total, other adverse events | 31 / 31 |
| serious Total, serious adverse events | 22 / 31 |
Outcome results
Primary
Overall Survival
To determine the overall survival of patients with hemophagocytic lymphohistiocytosis at 8 weeks after an ATG/etoposide-based induction regimen and to determine the feasibility of this approach in the context of a multicenter clinical trial.
Time frame: 8 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Therapy | Overall Survival | 25 Participants |
Secondary
Disease Status at BMT
To determine the rate of complete response at the time of BMT preparative regimen initiation
Time frame: up to day 180
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Therapy | Disease Status at BMT | 8 Participants |
Secondary
Number of Participants Who Experienced Reactivation
To determine the frequency of disease reactivation prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)
Time frame: up to 180 days
Population: all patients surviving to BMT or day 180 and achieving complete or partial response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Therapy | Number of Participants Who Experienced Reactivation | 4 Participants |
Secondary
Overall Survival
To determine overall survival prior to the initiation of BMT (bone marrow transplant) preparative regimen (or day 180, if BMT preparative regimen not yet begun)
Time frame: up to day 180
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Therapy | Overall Survival | 22 Participants |
Secondary
Overall Survival to Day +100
To determine overall survival to day +100 after BMT, for patients who have undergone BMT within 6 months of study entry
Time frame: up to day 280
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Therapy | Overall Survival to Day +100 | 9 Participants |
Secondary
Time to Response
To determine the median time to complete response during 8 weeks of therapy
Time frame: 8 Weeks
Population: Patients assessed for disease features and classified each week per definition of complete response in order to determine the time at which they achieved complete response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Induction Therapy | Time to Response | 4 weeks |