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Carlos E. B. Couri, MD, PhD; Maria C. B. Oliveira, MD; Ana B. P. L. Stracieri, MD, PhD; Daniela A. Moraes, MD; Fabiano Pieroni, MD, PhD; George M. N. Barros, MD; Maria Isabel A. Madeira, MD; Kelen C. R. Malmegrim, PhD; Maria C. Foss-Freitas, MD, PhD; Belinda P. Simões, MD, PhD; Edson Z. Martinez, PhD; Milton C. Foss, MD, PhD; Richard K. Burt, MD; Júlio C. Voltarelli, MD, PhD

JAMA. 2009;301(15):1573-1579.

Context  In 2007, the effects of the autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in 15 patients with type 1 diabetes mellitus (DM) were reported. Most patients became insulin free with normal levels of glycated hemoglobin A_1c (HbA_1c) during a mean 18.8-month follow-up. To investigate if this effect was due to preservation of beta-cell mass, continued monitoring was performed of C-peptide levels after stem cell transplantation in the 15 original and 8 additional patients.

Objective  To determine C-peptide levels after autologous nonmyeloablative HSCT in patients with newly diagnosed type 1 DM during a longer follow-up.

Design, Setting, and Participants  A prospective phase 1/2 study of 23 patients with type 1 DM (aged 13-31 years) diagnosed in the previous 6 weeks by clinical findings with hyperglycemia and confirmed by measurement of serum levels of anti–glutamic acid decarboxylase antibodies. Enrollment was November 2003-April 2008, with follow-up until December 2008 at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeirão Preto, Ribeirão Preto, Brazil. Hematopoietic stem cells were mobilized via the 2007 protocol.

Main Outcome Measures  C-peptide levels measured during the mixed-meal tolerance test, before, and at different times following HSCT. Secondary end points included morbidity and mortality from transplantation, temporal changes in exogenous insulin requirements, and serum levels of HbA_1c.

Results  During a 7- to 58-month follow-up (mean, 29.8 months; median, 30 months), 20 patients without previous ketoacidosis and not receiving corticosteroids during the preparative regimen became insulin free. Twelve patients maintained this status for a mean 31 months (range, 14-52 months) and 8 patients relapsed and resumed insulin use at low dose (0.1-0.3 IU/kg). In the continuous insulin–independent group, HbA_1c levels were less than 7.0% and mean (SE) area under the curve (AUC) of C-peptide levels increased significantly from 225.0 (75.2) ng/mL per 2 hours pretransplantation to 785.4 (90.3) ng/mL per 2 hours at 24 months posttransplantation (P < .001) and to 728.1 (144.4) ng/mL per 2 hours at 36 months (P = .001). In the transient insulin–independent group, mean (SE) AUC of C-peptide levels also increased from 148.9 (75.2) ng/mL per 2 hours pretransplantation to 546.8 (96.9) ng/mL per 2 hours at 36 months (P = .001), which was sustained at 48 months. In this group, 2 patients regained insulin independence after treatment with sitagliptin, which was associated with increase in C-peptide levels. Two patients developed bilateral nosocomial pneumonia, 3 patients developed late endocrine dysfunction, and 9 patients developed oligospermia. There was no mortality.

Conclusion  After a mean follow-up of 29.8 months following autologous nonmyeloablative HSCT in patients with newly diagnosed type 1 DM, C-peptide levels increased significantly and the majority of patients achieved insulin independence with good glycemic control.

Trial Registration  clinicaltrials.gov Identifier: NCT00315133

Author Affiliations: Departments of Clinical Medicine (Drs Couri, Oliveira, Stracieri, Moraes, Pieroni, Barros, Madeira, Malmegrim, Foss-Freitas, Simões, Foss, and Voltarelli) and Social Medicine (Dr Martinez), School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; and Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Dr Burt).

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