Immune Ablation Using Cyclophosphamide without Stem Cell Rescue for Intractable Multiple Sclerosis and Its Variants

Background: Multiple sclerosis (MS) is the most common progressively disabling neurologic disease of young adults worldwide. MS is a cytotoxic T Cell mediated disease with autoimmune-driven destruction occurring most actively in the early stages. Immune suppression with high dose steroids, cyclophosphamide (CTX), cladribine, and mitoxantrone has demonstrated benefit in intractable, more progressive or frequently relapsing patients, both on clinical and MRI parameters. In particular, non-ablative doses of CTX appear to stabilize progressive MS for one year or longer and were most effective earlier in the course of the disease. In aggressive MS deletion of cytotoxic T cells through immune ablation may offer a more durable remission than standard immune suppression. Due to aldehyde dehydrogenase mediated resistance of CD34+ cells to CTX, hematopoietic reconstitution without hematopoietic stem cell rescue is possible and could eliminate the need for stem cell mobilization which has been associated with disease flare and potential re-infusion of T-cells.

Objective: To assess the safety and efficacy of immunoablation using CTX without hematologic stem cell rescue for intractable relapsing progressive multiple sclerosis failing standard immune modulation or immune suppression.

Patients and Methods: Eight patients (median age = 29, range 24–37, men = 2, women = 6) between January 2005 and July 2008 underwent immunoablation with high dose CTX (HD-CTX) at 50 mg per kg per day intravenously for four consecutive days. Adequate hydration and forced diuresis were implemented to prevent hemorrhagic cystitis. G-CSF was started 6 days after the last dose of chemotherapy at 5 mcg/kg per day until the absolute neutrophil count was > 1000 per UL for two consecutive days. Red cell transfusions were administered to maintain hemoglobin of > 8 gm/dl and platelet transfusions were given to patients with < 10 Th/ul or to patients with active bleeding regardless of their platelet count. Clinical, laboratory, and MRI monitoring was scheduled at 3–6 month intervals over 24 months.

Results: Eight patients have been treated with HD-CTX since 2005 and six of these patients have been monitored for more than 2 years. Hematologic complications included grade 4 neutropenia in all patients (duration 9–18 days), grade 4 thrombocytopenia in all patients (duration 3–13 days in 5 patients; 3 patients were discharged prior to platelet recovery), and grade 3 anemia in 6 patients (duration 1–9 days). All 8 patients required platelet transfusion (mean = 3.85 units, range 1–13 units) and 7 patients required PRBC transfusion (mean = 1.625 units, range 0–4 units). Non-hematologic grade 3 or 4 complications included grade 3 neutropenic fever in 7 patients, grade 3 hematuria in 2 patients and CTX-induced cardiotoxity with troponin elevation and infective endocarditis in 1 patient. 1 pt had a dystonic reaction to compazine.

All patients have demonstrated improvements ranging from halting progression of MS clinically and radiologically to dramatic reductions of neurologic deficits, except in two patients whose disease reprogressed after 20 months of stability. One of these two patients demonstrated only subclinical disease activity on brain MRI without clinical correlates whereas the other experienced two milder clinical exacerbations. The latter has begun therapy with natalizumab, and the same has been recommended for the former. Given the refractory nature of these patients’ MS prior to therapy, the absence of further disease activity has been remarkable.

Conclusions: Immunoablation with HD-CTX without stem cell rescue in patients with intractable MS represents a reasonable treatment option. These patients had significant improvements ranging from amelioration to stabilization of the disease course as well as reduction of disabilities. HD-CTX was tolerable with acceptable side effects and full hematologic recovery without the use of stem cell rescue. This is particularly important in patients with MS because of the associated disease flare and potential re-infusion of T-cells with stem cell mobilization. More data is needed and this clinical trial continues to accrue patients.