Patient case: 11-year-old male with Peutz-Jeghers syndrome; genetic feature: STK11

Clinical trial: Hematopoietic Stem Cell Transplant in Devic's Disease

Summary: This study is designed to examine whether treating Devic's disease patients with high dose cyclophosphamide together with rabbit antithymocyte globulin (rATG)/rituximab (drugs which reduce the function of the immune system), followed by return of previously collected patient's stem cells will result in improvement in Devic's disease. Stem cells are undeveloped cells that have the capacity to grow into mature blood cells, which normally circulate in the blood stream. The purpose of the intense chemotherapy is to destroy the cells in patient's immune system, which may be causing his/her disease. The purpose of the stem cell infusion is to produce a normal immune system that will no longer attack patient's body. The purpose of study is to examine the safety and efficacy of this treatment. The drugs used in this study treatment are drugs for commonly used for immune suppression.

Detailed description: Neuromyelitis optica (NMO, Devic's disease) is an autoimmune, inflammatory, demyelinating central nervous system disorder in which a person's own immune system attacks the optic nerves and spinal cord and is characterized by concurrence of optic neuritis and transverse myelitis, typically associated with a lesion in the spinal cord extending over three or more vertebral segments. Although it is most commonly relapsing, it is distinct from multiple sclerosis in that it is more severe, tends to spare the brain, and is associated with a longitudinally extensive lesion on spinal cord MRI. Furthermore, NMO is associated with a highly specific serum autoantibody marker, NMO-immunoglobulin G (IgG), which targets the water channel aquaporin-4. The disease follows a relapsing course in more than 90% of patients.
  At present, parenteral corticosteroids are widely employed as first-line treatment of optic neuritis and myelitis attacks, whereas therapeutic plasmapheresis is applied in the case of corticosteroids failure. Various strategies for the prevention of NMO relapses have been employed in small case series with modest activity. Immune based therapies, in order to be effective, need to be started early in the disease course while Devic's disease is predominantly an immune-mediated and inflammatory disease. Since 50% of patients with NMO are confined to a wheelchair within 5 years of onset, new therapies are needed in this disease.
  We now propose, as a phase I study, complete immune ablation and subsequent reconstitution with autologous stem cells.
  Based on the experience of the pilot studies, the current protocol will mobilize stem cells with granulocyte-colony stimulating factor (G-CSF) and cyclophosphamide and collect stem cells by apheresis. A subsequent bone marrow harvest will be performed only if needed to supplement the peripheral blood stem cells (PBSC). Based on experience of autoimmune flares in patients receiving G-CSF alone for mobilization, patients will be mobilized with cyclophosphamide 2.0 g/m2 and G-CSF 5- 10 mcg /kg.
  In order to avoid cumulative cardiac toxicity from cyclophosphamide and to allow culture of hematopoietic stem cell (HSC) product, three weeks must separate the administration of cyclophosphamide for mobilization and for conditioning.
  Cyclophosphamide 50 mg/kg/day will be given IV over 2 hours in 500 cc of normal saline. If actual weight is < ideal weight, cyclophosphamide will be given based on actual weight. If actual weight is > ideal weight, cyclophosphamide will given as adjusted weight. Adjusted weight = ideal weight + 25% (actual weight minus ideal weight).
  Hydration-guidelines, normal saline (NS) at 150-200 ml/hr should be given 2 hours before cyclophosphamide and continued until 24 hours after the last cyclophosphamide dose. The rate of hydration will be aggressively adjusted. Twice daily weights will be obtained. Amount of fluid can be modified based on patient's fluid status.
  r ATG 0.5 mg/kg given on day -5, then 1.0 mg/kg given on day -4, then 1.5 mg/kg given on days -3 through -1. rATG is infused over 10 hours. Premedicate with Acetaminophen 650 mg po and Diphenhydramine 25 mg po/IV 30 minutes before the infusion.
  Rituxan ( Rituximab ) - The dose of 500 mg of Rituximab will be diluted in 500 ml 0.9 % NS and infused per standard Rituximab infusion guidelines, given on days -6 and on day + 1. Following the guidelines, Rituximab will be started at 50 mg/hr. If no reaction occurs, the dose will be increased by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr.
  G-CSF - guidelines, 5-10 mcg/kg/day will be started day + 5 and continued until the absolute neutrophil counts reaches at least 1,000/µl.

Eligibility: Inclusion Criteria:
  -  Age between 16-65, at the time of pretransplant evaluation
  -  An established diagnosis of Devic's disease (more than one acute attack)
  -  NMO- IgG aquaporin-4 autoantibody positive
  Exclusion Criteria:
  -  Paraplegia or quadriplegia and legal blindness (defined as visual acuity of 20/200 or less in the better eye with the best correction possible)
  -  Any illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy
  -  Prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix. Other malignancies for which the patient is judged to be cured, such as head and neck cancer, or breast cancer will be considered on an individual basis
  -  Positive pregnancy test
  -  Inability or unwillingness to pursue effective means of birth control. Effective birth control is defined as 1) refraining from all acts of vaginal intercourse (ABSTINENCE); 2) consistent use of birth control pills; 3) injectable birth control methods (Depo-provera, Norplant); 4) tubal sterilization or male partner who has undergone vasectomy; 5) placement of an intrauterine device (IUD); or 6) use, with every act of intercourse, of diaphragm with contraceptive jelly and/or condoms with contraceptive foam
  -  Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
  -  forced expiratory volume at one (FEV1) / forced vital capacity (FVC) < 60% of predicted after bronchodilator therapy (if necessary)
  -  Diffusing capacity of lung for carbon monoxide (DLCO) < 50% of predicted
  -  Resting left ventricular ejection fraction (LVEF) < 50 %
  -  Serum creatinine > 2.0 mg/dl
  -  Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins
  -  Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
  -  Bilirubin > 2.0 mg/dl
  -  Platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul
  -  Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with treatment or informed consent impossible
  -  Active infection except asymptomatic bacteriuria
  -  Inability to give informed consent
  -  HIV positive
  -  Transaminases > 3x of normal limits, liver cirrhosis

Relevance to patient case: not relevant