Autologous Stem Cell Transplant for Neurologic Autoimmune Diseases

High-Dose Immunosuppressive Therapy Using Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) + Thymoglobulin Followed by Syngeneic or Autologous Hematopoietic Cell Transplantation for Patients With Autoimmune Neurologic Diseases

This phase II trial studies the side effects and how well carmustine, etoposide, cytarabine and melphalan together with antithymocyte globulin before a stem cell transplant works in treating patients with autoimmune neurologic disease that did not respond to previous therapy. In autoimmune neurological diseases, the patient's own immune system 'attacks' the nervous system which might include the brain/spinal cord and/or the peripheral nerves. Giving high-dose chemotherapy, including carmustine, etoposide, cytarabine, melphalan, and antithymocyte globulin, before a stem cell transplant weakens the immune system and may help stop the immune system from 'attacking' a patient's nervous system. When the patient's own (autologous) stem cells are infused into the patient they help the bone marrow make red blood cells, white blood cells, and platelets so the blood counts can improve.

Study Overview

• Status: Active, not recruiting
• Conditions: Myasthenia Gravis; Neuromyelitis Optica; Autoimmune Disease; Chronic Inflammatory Demyelinating Polyneuropathy; Lambert Eaton Myasthenic Syndrome; Cerebellar Degeneration; Stiff Person Syndrome; Opsoclonus Myoclonus Syndrome; Neurologic Autoimmune Disease; Autologous Transplant Autoimmune; Multiple Sclerosis Transplant; MS Stem Cell Transplant; Multiple Sclerosis Stem Cell Transplant; HCT for Neurologic Autoimmune Disorders; CIDP Transplant; Myasthenia Gravis Transplant; Autoimmune Nervous System Disorder; Central Nervous System Vasculitis; Rasmussen Subacute Encephalitis
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Etoposide; Drug: Cytarabine; Drug: Prednisone; Drug: Melphalan; Drug: Carmustine; Biological: Anti-Thymocyte Globulin; Procedure: Syngeneic Bone Marrow Transplantation; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation

Detailed Description

OUTLINE:

Patients receive carmustine intravenously (IV) on day -6, etoposide IV and cytarabine IV twice daily (BID) on days -5 to -2, melphalan IV on day -1, and antithymocyte globulin IV on days -2 and -1. Patients then undergo autologous or syngeneic stem cell transplant on day 0. Patients also receive prednisone orally (PO) once daily (QD) on days 7-21, followed by 2 week taper.

After completion of study treatment, patients are followed up at 3 months, 1 year, and then annually thereafter for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bernie McLaughlin; Phone Number: 206.667-4916; Email: bmclaugh@fredhutch.org

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium
    • Seattle, Washington, United States, 98122-4307
      • Swedish Medical Center-First Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 71 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with an autoimmune disorder of the central or peripheral nervous system will be eligible; this will include:

  • Primary Central Nervous System (CNS) vasculitis
  • Rasmussen's encephalitis
  • Autoimmune peripheral neuropathy (anti-Hu [Anna-1], anti-GM1 [GD1b], anti-MAG, anti-ganglioside, anti-sulfatide)
  • Autoimmune cerebellar degeneration
  • Gait Ataxia with Late age Onset Polyneuropathy (GALOP)
  • Stiff Person Syndrome
  • Chronic Inflammatory Demyelinating Polyneuropathy
  • Myasthenia Gravis
  • Lambert-Eaton myasthenic syndrome
  • Human T-cell lymphotropic virus (HTLV)-1-associated myelopathy (HAM) / tropical spastic paraparesis (TSP)
  • Opsoclonus/myoclonus (anti-Ri)
  • Neuromyelitis optica
  • Multiple sclerosis
  • Other central or peripheral nervous system autoimmune diseases as approved by study neurologists and the Fred Hutchinson Cancer Research Center (FHCRC) faculty at Patient Care Conference (PCC)
• Patients must satisfy the criteria for a diagnosis of one of the severe neurological autoimmune disorders outlined
• Patients age =< 70 years
• Evidence of disease activity as outlined (e.g. gadolinium enhancement on magnetic resonance imaging of the brain or clinical progression)
• Patients must have failed at least 2 lines of standard therapy as outlined for the specific diseases
• DONOR: Sibling of any patient enrolled on this protocol proven by ABO typing, human leukocyte antigen (HLA) typing and variable number tandem repeat (VNTR) analysis to be syngeneic with the patient (e.g. identical twin)
• DONOR: Willing to undergo multiple apheresis procedures (except donors < 12 years who will undergo bone marrow harvests)

Exclusion Criteria:

• Age >= 71 years
• Pregnancy or expressed plans to become pregnant within 1 year of the procedure
• Patients who are serologically positive for human immunodeficiency virus (HIV)

• Patients with pulmonary, cardiac, hepatic or renal impairment that would limit their ability to receive cytoreductive therapy and compromise their survival; this should include patients with any of the following:

  • Severe pulmonary dysfunction associated with a carbon monoxide diffusing capacity (DLCO) (corrected for hemoglobin) < 60%, or requires supplemental oxygen; patients who are unable to perform pulmonary function test (because of underlying disease) will be excluded if the oxygen saturation is < 92% on room air
  • Uncontrolled malignant arrhythmias, or clinical evidence of congestive heart failure (New York class III-IV) or ejection fraction < 50%
  • Renal disease with estimated glomerular filtration rate (GFR) by creatinine clearance or iothalamate clearance < 50 ml/min/1.73 m^2 body surface area
  • Serum glutamate pyruvate transaminase (SGPT)/aspartate aminotransferase (AST) > 3 times normal or direct bilirubin greater than 2.5 mg/dL on two repeated tests
• Active uncontrolled infection
• Demonstrated lack of compliance with prior medical care
• Patients whose life expectancy is limited by illness other than their neurological condition
• Patients with evidence of myelodysplasia
• Active malignancy (excluding localized squamous cell or basal cell carcinoma of the skin)
• DONOR: Inadequate documentation that donor and recipient are syngeneic
• DONOR: Donors who do not fulfill criteria as apheresis donors as established by institutional guidelines
• DONOR: Concordant for autoimmune neurological disease(s) as determined by neurological evaluation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (immunosuppressive therapy followed by transplant); Patients receive carmustine IV on day -6, etoposide IV and cytarabine IV BID on days -5 to -2, melphalan IV on day -1 and antithymocyte globulin IV on days -2 and -1. Patients then undergo autologous or syngeneic stem cell transplant on day 0. Patients also receive prednisone PO QD on days 7-21, followed by 2 week taper.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Etoposide; Given IV; Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside; EPEG; Lastet; Toposar; Vepesid; VP 16-213; VP-16; VP-16-213; 33419-42-0; Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosar-U; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; 147-94-4; Drug: Prednisone; Given PO; Other Names: Deltasone; Orasone; .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Panafcort; Panasol-S; Paracort; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisonum; Prednitone; Promifen; Servisone; SK-Prednisone; 53-03-2; Drug: Melphalan; Given IV; Other Names: CB-3025; L-PAM; L-Sarcolysin; Alanine Nitrogen Mustard; L-Phenylalanine Mustard; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; 148-82-3; Drug: Carmustine; Given IV; Other Names: BCNU; BiCNU; Becenum; Becenun; Bis(chloroethyl) Nitrosourea; Bis-Chloronitrosourea; Carmubris; Carmustin; Carmustinum; FDA 0345; N,N'-Bis(2-chloroethyl)-N-nitrosourea; Nitrourean; Nitrumon; SK 27702; SRI 1720; WR-139021; Gliadel; 154-93-8; Biological: Anti-Thymocyte Globulin; Given IV; Other Names: ATGAM; ATG; Antithymocyte Globulin; Antithymocyte Serum; ATS; Thymoglobulin; Procedure: Syngeneic Bone Marrow Transplantation; Undergo syngeneic bone marrow transplantation; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous or syngeneic stem cell transplantation; Other Names: Autologous Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo autologous or syngeneic stem cell transplantation; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of grades 4-5 regimen-related toxicity	Assessed by the Regimen Related Toxicity Scale. Using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The development of a grade 4 to 5 toxicity of any of the included major organ systems within the first 365 days after transplant will be defined as regimen-related toxicity.	Up to 1 year post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transplant-related mortality	Defined as death within the first 100 days of transplant due to transplant-related complications.	Within 100 days post-transplant
Disease responses	Assessed by clinical, laboratory and radiologic evaluation	Up to 5 years
Engraftment kinetics	Monitored for engraftment kinetics of granulocytes, platelets and red cells post-transplant.	Over first 60 days post-transplant
Number of subjects achieving greater than or equal to 4.0 x 10^6 CD34+ cells/kg, after up to two peripheral blood stem cell mobilizations	Efficacy of peripheral blood stem cell mobilization as evaluated by total number of harvested CD34+cells/kg, for autologous transplant.	Baseline to post mobilization, assessed up to 20 days after starting final mobilization (up to two mobilizations)
Number of subjects with an exacerbation of autoimmune disease symptoms secondary to G-CSF (filgrastim) during peripheral blood stem cell mobilization	Subjects are evaluated by standardized clinical neurologic tests specific to autoimmune disease type.	Baseline to post mobilization, assessed up to 20 days after starting final mobilization (up to two mobilizations)

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Investigators: Principal Investigator: Leona Holmberg, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): January 31, 2030

Study Registration Dates

• First Submitted: July 15, 2008
• First Submitted That Met QC Criteria: July 15, 2008
• First Posted (Estimated): July 16, 2008

Study Record Updates

• Last Update Posted (Estimated): February 5, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Stiff Person Syndrome; neurologic autoimmune disease; autologous transplant autoimmune; multiple sclerosis transplant; MS stem cell transplant; multiple sclerosis stem cell transplant; HCT for neurologic autoimmune disorders; CIDP transplant; myasthenia gravis transplant
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Immune System Diseases; Neoplasms; Demyelinating Autoimmune Diseases, CNS; Demyelinating Diseases; Neoplasms by Site; Eye Diseases; Neurologic Manifestations; Disease Attributes; Disease; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Manifestations; Dyskinesias; Spinal Cord Diseases; Nervous System Neoplasms; Optic Nerve Diseases; Cranial Nerve Diseases; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Myelitis, Transverse; Optic Neuritis; Polyradiculoneuropathy; Chronic Disease; Neuroinflammatory Diseases; Multiple Sclerosis; Sclerosis; Syndrome; Encephalitis; Muscle Weakness; Nervous System Diseases; Myasthenia Gravis; Neuromyelitis Optica; Polyneuropathies; Autoimmune Diseases; Vasculitis; Autoimmune Diseases of the Nervous System; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Lambert-Eaton Myasthenic Syndrome; Vasculitis, Central Nervous System; Ocular Motility Disorders; Stiff-Person Syndrome; Myoclonus; Opsoclonus-Myoclonus Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Keratolytic Agents; Etoposide; Etoposide phosphate; Podophyllotoxin; Prednisone; Melphalan; Cytarabine; Carmustine; Cortisone; Thymoglobulin; Antilymphocyte Serum; Mechlorethamine; Nitrogen Mustard Compounds
• Other Study ID Numbers: 2260.00 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2010-00403 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RG9213030 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)