High Dose Cyclophosphamide Without Stem Cell Transplantation in Systemic Sclerosis

Purpose: Recently, high dose cyclophosphamide (CYC) without bone marrow transplantation has been employed as a method to induce durable treatment-free remissions in severe aplastic anemia and a variety of other severe autoimmune disorders. We present our initial experience in treating early active severe systemic sclerosis (SSc) using high dose CYC without stem cell rescue.
Methods: We treated a total of 4 patients with early active severe SSc in an open label study protocol. All of the patients received 50 mg/kg of cyclophosphamide daily for four consecutive days followed by 5 μg/kg granulocyte colony stimulating factor until the neutrophil count was 1 x 10⁹/Liter for two consecutive days. The primary outcome was the modified Rodnan skin score (mRSS) and successful therapy was considered a greater than 25% improvement. Other outcome measures include the physician global assessment (PGA) score, Health Assessment Questionnaire (HAQ) and pulmonary function tests. Systemic disease including pulmonary function was monitored. An additional patient is reported who was treated using this method in their local community.
Results: Three of the four patients were considered a treatment success with a reduction of mRSS of 41%, 45%, and 59% within one month of therapy (table). One of the four patients died at week 7 secondary to a lung infection following marrow recovery. The secondary outcomes, the PGA and HAQ scores also improved in all three evaluable patients (table). The Forced Vital Capacity (FVC) remained stable (+/- 10% absolute value). Patient 1 and 3 have had no flare of disease after 25 months and 8 months follow-up, respectively. After 12 months of no disease activity, patient 2 re-flared with new skin disease on the fingers, hands and arms (mRSS increase from 5 to 13). Three of the four patients had a neutropenic fever. Among the three evaluable patients, no other significant adverse reactions were seen. The median time to 0.5 x 10⁹/Liter neutrophils after CYC treatment was 15 days (range 14-17 days). The median number of packed red blood cell transfusions was 7 (range 0 to 25) and platelet transfusions were 4 (range 1 to 9). The community based case also responded with a fall in the skin score of 21 to 6 after therapy and a sustained period of no active disease for now 20 months. This community based case had an improvement in FVC from 2.88 (85%) pre-treatment to 3.35 (100%) 1 year after treatment.

Evaluable Patients	*Pre-CYC Treatment	Post CYC 1 Month	Post CYC 3 Months	Post CYC 6 Months	Post CYC 12 Months	Post CYC 24 Months
**mRSS
Patient 1	27	11	14	---	7	7
2	22	10	6	5	13	#
3	17	10	4	2	#	#
***PGA
Patient 1	70	37	26	---	---	---
2	87	27	21	14	75	#
3	59	26	19	13	#	#
HAQ
Patient 1	1.25	---	0.875	---	---	0.875
2	1.875	1.625	0.5	0.5	0.5	#
3	1.25	1.00	0	0.125	#	#
****FVC
Patient 1	3.55 (79%)	---	4.46 (87%)	---	4.25 (84%)	4.12 (81%)
2	2.63 (72%)	---	---	3.39 (79%)	3.19 (75%)	#
3	5.45(120%)	---	---	5.14 (96%)	#	#
*Pre-CYC is a baseline measurement prior to cyclophosphamide treatment ** Modified Rodnan Skin Score *** Physician Global Assessment scale of 0 (best)-100(worse) mm **** Forced Vital Capacity Liters (%Predicted) ---missing data # patient has not reached this assessment point

Conclusions: High dose CYC without stem cell transplantation leads to rapid improvement of the modified Rodnan skin, HAQ, and PGA sores in the severe early diffuse SSc. These data support the need for further clinical investigation of the role for high dose CYC alone in the treatment of SSc.

 C.V. Tehlirian, None; L.K. Hummers, None; E. Forbes, None; R.A. Brodsky, None; F.M. Wigley, None.