Preliminary Toxicity Profile of High-Dose Cyclophosphamide for Severe, Refractory Multiple Sclerosis. IND: 65863.
Authors: Seth Rahul , Chandra Sumeet , Michelle Stevens , Emily Locher , Kenneth Zamkoff , Gladstone Gladstone E. 
Published: April 2020

Abstract
Introduction: The use of potentially lethal doses of chemotherapy for non-malignant illnesses is often met by clinicians and patients with great apprehension. High-dose cyclophosphamide is a non-bone marrow transplant treatment option for those afflicted by severe-refractory autoimmune illnesses mediated by autoreactive lymphocytes. The goal of this therapy is to eradicate offending autoreactive B and T cells but to spare the pleuripotent blood stem cell of any ill effect and obviate the need for stem cell rescue.
While cyclophosphamide dosed at 50mg/kg/day for four consecutive days is a standard off-label dosing schedule common in bone marrow transplantation, the FDA required cyclophosphamide, in this setting, to be considered as an investigational new drug (IND). Here we report the toxicity data on our first six patients with severe, refractory multiple scleroses treated with high-dose cyclophosphamide without stem-cell rescue. It is our goal to enroll 25 patients under this IND.
Materials and Methods: Patients were diagnosed with MS by established criteria. All had an extended disability status scale (EDSS) score of ≥3.5 after two standard treatment regimens, a left ventricular ejection fraction of ≥ 45% and a serum creatinine ≤3mg/dL. All patients signed an informed consent approved by the Stony Brook University IRB. Patients received 200mg/kg of cyclophosphamide over fours days. Forced diuresis and MESNA were used for hemorrhagic cystitis prophylaxis. Patients received prophylactic acyclovir, fluconazole and Bactrim. Neutropenic fevers received broad-spectrum antimicrobials. Hematocrits were maintained above 25% and platelets were maintained above 10 x 109/L. Starting on day +10, filgrastim (5mcg/kg/day) was used until evidence of neutrophil recovery.
Results: Six patients with a median age of 43 (range: 40–48) years, a median EDSS score of six (range: 4–8) and a median duration of disease for 14 (range: 6–18) years participated in this protocol. Patients experienced absolute neutropenia for a median of 8.5 (range: 6–10) days, received a median of 0.7 (range: 0–2) units of PRBCs and a median of 1.5 (range: 0–2) single unit donor platelet infusions.
All patients tolerated treatment very well with only expected toxicities. All patients experienced nausea and vomiting with a maximum toxicity grade of 3, controlled with anti-emetics. Stomatitis was common with a maximum toxicity grade of 3. None required parenteral support. Transient, grade 1, liver enzymes elevation was common. Serum chemistries abnormalities were transient and corrected with fluids and electrolyte administration. Given a median follow-up of 125 (range: 40–230) days it is too early to comment on the long-term anti-MS effects; in early follow-up, five patients remain off all immunomodulatory medications and no patient has incurred a major MS exacerbation.
Discussion: High-dose cyclophosphamide without stem-cell rescue studied under IND 65863 appears to be well tolerated and safe. All patients experienced full and spontaneous hematopoietic recovery without stem-cell rescue, thereby eliminating the possibility of accidental autoreactive lymphocyte infusion. We have previously reported a median of 9.5 days (range: 6–15) of absolute neutropenia in a conglomerate of other patients with severe refractory autoimmune illnesses treated in a similar fashion.
Conclusion: This data suggests that MS patients treated with high-dose cyclophosphamide do not experience a unique toxicity profile. This data was provided to the FDA.