High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) Study

National Institute of Allergy and Infectious Diseases (NIAID)25 enrolled

Overview

The purpose of this study is to determine the effectiveness of a new treatment for multiple sclerosis (MS), a serious disease in which the immune system attacks the brain and spinal cord. MS can be progressive and severe and lead to significant disability. The study treatment involves the use of high-dose chemotherapeutic drugs to suppress the immune system. The participant's own (autologous) blood-forming (hematopoietic, CD34+) stem cells are collected before the chemotherapy is given, and then transplanted back into the body following treatment. Transplantation of autologous hematopoietic stem cells is required to prevent very prolonged periods of low blood cell counts after the high-dose chemotherapy.

MS is a chronic autoimmune disease of the central nervous system in which myelin, the protective coat that surrounds nerve cells, is damaged or destroyed by autoimmune T cells and macrophages, leading to an eventual loss of neurologic function. In a pilot study in Europe using high-dose chemotherapy, it was observed that 18 of 19 MS patients stabilized or improved clinically, and only one patient showed a new lesion on magnetic resonance imaging (MRI) of the brain at 4.5 years after treatment. Improvement was seen in quality-of-life assessments. In ITN033AI, high-dose chemotherapy with autologous CD34-selected hematopoietic cell transplantation will be given to confirm the results from the pilot study and to offer therapy to patients with early MS and a poor prognosis. Research studies will be performed in addition to clinical assessments to better understand the effect of the treatment on the activity of MS. High-dose chemotherapy will be used to deplete autoreactive immune cells. These regimens also deplete the bone marrow, the source of blood-forming CD34+ stem cells which causes very low blood counts. Therefore, the participant's autologous CD34+ hematopoietic stem cells will be collected before high dose immunosuppressive therapy is given and then returned as a transplant post-chemotherapy. Patients will be followed closely after the autologous transplantation since they will be at risk for infections after treatment. At the beginning of the study, participants will undergo a number of screening and baseline procedures, including a physical exam, blood collection, MS-confirming neurology exams and questionnaires, and MRI procedures. Participants will be given prednisone and granulocyte-colony stimulating factor (G-CSF) to mobilize CD34+ hematopoietic stem cells from the bone marrow into the peripheral blood. When the peripheral blood CD34+ cell count reaches 20,000 cells/ml or greater, these cells will be collected by leukapheresis. In this process, a catheter is placed into a large blood vessel, peripheral blood is withdrawn, and a high speed sedimentation (leukapheresis) device is used to separate and retain the cells required for autologous transplantation. Other blood cells are then returned to the participant's body. In the laboratory, the CD34+ hematopoietic stem cell graft will be selected and prepared from the leukapheresis collection, and stored until needed for transplant. Seven or more days following the collection of their autologous graft, participants will be hospitalized and receive high-dose chemotherapy consisting of carmustine, etoposide, cytarabine, and melphalan (BEAM) and thymoglobulin. This is followed by transplantation of the autologous hematopoietic cell graft. Participants will remain in the hospital for observation during recovery of their peripheral blood cell counts, as described in the protocol. Participants will receive G-CSF and blood transfusions, if needed, and will be monitored for infections. Following discharge from the hospital, eight study visits will occur over sixty months (five years). During these visits, participants will undergo blood and urine collection, MRI studies, leukapheresis, and MS neurology exams and will complete questionnaires.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of relapsing-remitting or progressive-relapsing multiple sclerosis for less than 15 years using McDonald Criteria. More information on this criterion can be found in the protocol * Score between 3.0 and 5.5 on the Expanded Disability Status Scale (EDSS) * T2 abnormalities on brain MRI consistent with MS * Two or more relapses in 18 months time on interferon (IFN), glatiramer acetate (GA), natalizumab or cytotoxic therapy with EDSS increase of 1.0 or greater for participants with EDSS at screening of 3.0 to 3.5 (0.5 or greater for participants with EDSS at screening of 4.0 to 5.5) sustained at least 4 weeks after at least one of these relapses OR one relapse on IFN, GA, natalizumab or cytotoxic therapy with EDSS increase of 1.5 or greater (1.0 for subjects with EDSS at screening of 5.5) sustained at least 4 weeks, together with MRI changes consistent with poor prognosis. More information on this criterion can be found in the protocol. * On IFN or GA for at least 6 months before the relapses occur that are counted to satisfy previous inclusion criterion OR have received adequate doses of natalizumab or cytotoxic therapy on a treatment schedule before the relapses occur that are counted to satisfy previous inclusion criterion * Approval by an MS Review Panel to participate in the study. More information on this criterion can be found in the protocol * In good clinical condition with adequate organ function and without coexisting medical problems that would increase the risk to the participant * Willing to use acceptable methods of contraception * Willing and able to comply with all study requirements and * Willing to accept and comprehend irreversible sterility as side effect of therapy. Exclusion Criteria: * Primary progressive MS * Secondary progressive MS without relapses (i.e., progression without exacerbations or relapses) for 12 or more months * Neuromyelitis optica, a disease similar to MS * Initiation of new immunosuppressant treatment after the participant becomes eligible for the protocol or continuance of immunosuppressant drugs after the participant is screened for the protocol. Treatment with IFN, GA, or corticosteroids is permitted after the participant becomes eligible for the protocol. * Lapse of greater than 6 months between the time a participant is eligible for the protocol and initiation of protocol treatment except when judged acceptable by the MS Review Panel * Prior treatment with investigational immunosuppressive agents within 3 months of study eligibility * Positive baseline plasma and CSF testing for JC virus or a brain MRI that has changes consistent with a diagnosis of progressive multifocal encephalopathy (PML) * History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS) * Active hepatitis B or C infection, cirrhosis, or HIV infection * Uncontrolled diabetes mellitus * Uncontrolled viral, fungal, or bacterial infection. Patients with asymptomatic bacteriuria are not excluded * Any illness that would jeopardize the ability to tolerate aggressive chemotherapy * Prior history of malignancy, except localized basal cell or squamous skin cancer. Other malignancies for which the subject is judged cured by the administered therapy will be considered on an individual basis. * Hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins or to iron compounds/medications * Metallic objects implanted in the body that would affect MRI exams * Psychiatric illness, mental deficiency, or cognitive dysfunction or * Pregnancy.

Outcomes

Primary Outcomes

Event-Free Survival Probability During the 5 Years After Transplant

Event-free survival (EFS) is survival without death or disease activity from any one of the following criteria: 1) loss of neurological function, defined as a change in pretransplant Extended Disability Status Scale (EDSS) of \> 0.5. 2) Relapse, defined as the development of a new neurological sign and corresponding symptom, or worsening of an existing neurological sign and symptom, localized to central nervous system white matter, resulting in neurological deficit/disability, and lasting over 48 hours. 3) New lesions on magnetic resonance imaging (MRI), defined as presence of 2 or more independent multiple sclerosis brain lesions detected on MRI 1 year or more after stem cell transplant. Kaplan-Meier estimates of survival probability, with 90% confidence interval based on Greenwood's formula for standard error.

Time frame: 5 years

Secondary Outcomes

Event-Free Survival Probability During the 3 Years After Transplant

Time frame: 3 years

Survival From Treatment-Related Mortality

The probability that a participant did not experienced a treatment-related death estimated at 1, 2, 3, 4, and 5 years following transplant via the Kaplan-Meier Method. Greenwood's formula for standard error was used to calculate 90% confidence intervals. Participants that did not experience a treatment-related death were censored at the time of last follow-up. A treatment-related death was defined as death that occurred at any time after study entry and that was possibly, probably, or definitely related to the cellular product or possibly, probably, or definitely related to mobilization of autologous peripheral blood hematopoietic progenitor cells with G-CSF and prednisone or to the high-dose immunosuppressive therapy. There were no treatment-related mortality events in the study.

Time frame: From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years

Overall Survival

The probability that a participant did not experienced a death estimated at 1, 2, 3, 4, and 5 years following transplant via the Kaplan-Meier Method. Greenwood's formula for standard error was used to calculate 90% confidence intervals. Participants that did not die were censored at the time of last follow-up.

Time frame: From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years

Survival From MS-Related Mortality

The probability that a participant did not experienced a MS-related death estimated at 1, 2, 3, 4, and 5 years following transplant via the Kaplan-Meier Method. Greenwood's formula for standard error was used to calculate 90% confidence intervals. Participants that did not experience a MS-related death were censored at the time of last follow-up. A MS-related death was defined as death that occurred at any time after study entry and that was possibly, probably, or definitely related to disease progression.

Time frame: From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years

Percent of Participants Who Experienced All-Cause Morbidity

Morbidity is the occurrence of NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 adverse event grade 3 or higher.

Time frame: From the time of enrollment until completion of the 5-year follow-up, an average of 6 years.

Percent of Participants Who Experienced All-Cause Morbidity Within 12 Months of Post-HCT

Morbidity is the occurrence of NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 adverse event grade 3 or higher.

Time frame: From the time of Autologous CD34+ Hematopoietic Stem Cell Transplant (HCT) to 1 year after HCT.

Time to Neutrophil Engraftment

Neutrophil engraftment, or neutrophil count recovery, is defined as an Absolute Neutrophil Count (ANC) \> 500/ μL for 2 consecutive measurements on different days. Normal range is 1500 to 8000/μL. Reference: http://www.medicinenet.com

Time frame: From time of graft infusion to time of engraftment, up to 6 years

Time to Platelet Engraftment

Platelet engraftment, or platelet count recovery, is defined as Platelets \> 20,000/μL for two consecutive measurements on different days with no platelet transfusions in the preceding 7 days. Normal range is 150,000-450,000/μL. Reference: http://www.hopkinsmedicine.org/heart\_vascular\_institute/clinical\_services/centers\_excellence/womens\_cardiovascular\_health\_center/patient\_information/health\_topics/platelets.html.

Time frame: From time of graft infusion to time of engraftment, up to 6 years

Event-Free Survival Probability After Transplant

Time frame: 1, 2, and 4 years after HCT

MS Progression-Free Survival Probability After Transplant

MS progression is measured as number of days from transplant to first Kurtzke's Expanded Disability Status Scale (EDSS) increase of more than 0.5 relative to the baseline measurement. EDSS assesses disability in Multiple Sclerosis patients. Eight functional systems are evaluated: visual, brain stem, pyramidal, cerebellar, sensory, bowel and bladder, cerebral, and ambulation. The overall score ranges from 0 (normal neurological exam) to 10 (death due to MS). Kaplan-Meier estimates of survival probability, with 90% confidence intervals based on Greenwood's formula for standard error.

Time frame: 1 to 5 years after HCT

MRI Activity-Free Survival Probability After Transplant

MS disease activity is measured as days from transplant to first occurrence of \>= 2 new MS lesions on Magnetic resonance imaging (MRI) relative to baseline. Kaplan-Meier estimates of survival probability, with 90% confidence intervals based on Greenwood's formula for standard error.

Time frame: 1 to 5 years after HCT

MS Relapse-Free Survival Probability After Transplant

MS clinical relapse is defined as the development of a new neurological sign and corresponding symptom, or worsening of an existing neurological sign and symptom, localized to central nervous system white matter, resulting in neurological deficit or disability, and lasting over 48 hours. Clinical relapse was determined by the participant's neurologist and was measured as days from transplant to new or worsening neurological symptom relative to baseline. Kaplan-Meier estimates of survival probability, with 90% confidence interval based on Greenwood's formula for standard error.

Time frame: 1 to 5 years after HCT

Disease-Modifying Therapy Survival Probability After Transplant

Treatment with disease-modifying therapy was measured by the number of days from transplant to the first treatment with an additional disease-modifying therapy. Examples of therapy include interferon beta-1a, glatiramer acetate, natalizumab, alemtuzumab, other immunosuppressive medications, or experimental therapies directed against MS activity. Kaplan-Meier estimates of survival probability, with 90% confidence interval based on Greenwood's formula for standard error.

Time frame: 1 to 5 years after HCT

Change From Baseline in Extended Disability Status Scale (EDSS)

Kurtzke's Expanded Disability Status Scale (EDSS) assesses disability in Multiple Sclerosis patients. Eight functional systems are evaluated: visual, brain stem, pyramidal, cerebellar, sensory, bowel and bladder, cerebral, and ambulation. The overall score ranges from 0 (normal neurological exam) to 10 (death due to MS). Change from baseline was computed as the value at the time point minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. A change of \> 0.5 in EDSS was a treatment-failure criterion.

Time frame: 6 months to 5 years after HCT

Change From Baseline in Number of Gadolinium-Enhanced Lesions

Multiple sclerosis disease-related lesions were assessed by gadolinium-enhanced magnetic resonance imaging (MRI). Change from baseline was computed as the value at the time point minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening.

Time frame: 8 weeks to 5 years after HCT

Number of New T2-Weighted Lesions From Baseline

A T2-weighted magnetic resonance imaging (MRI) scan was used to determine the number of new T2 lesions in the brain relative to Baseline. A value of 0 means that the participant didn't worsen. Values greater than 0 indicate an increase in disease activity from baseline.

Time frame: 6 Months to 5 years after HCT

Change From Baseline in T2-Weighted Lesion Volume

A T2-weighted magnetic resonance imaging (MRI) scan was used to assess the volume of T2 lesions in the brain. Change from baseline was computed as the value at the time point minus the baseline value.

Time frame: 8 weeks to 5 years after HCT

Change From Baseline in T1-Weighted Lesion Volume

A T1-weighted magnetic resonance imaging (MRI) scan was used to assess the volume of T1 lesions in the brain. Change from baseline was computed as the value at the time point minus the baseline value.

Time frame: 8 weeks to 5 years after HCT

Percent Change From Screening in Brain Volume

Magnetic resonance imaging (MRI) scan techniques measured ventricular volumes and grey and white matter brain volumes. Change from screening was computed as the value at the time point minus the screening value.

Time frame: 8 weeks to 5 years after HCT

High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) Study

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes