Stanford BIOC 230 - Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus

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PRELIMINARYCOMMUNICATIONAutologous NonmyeloablativeHematopoietic Stem Cell T ransplantationin Newly Diagnosed Type 1 Diabetes MellitusJu´ lio C. Voltarelli, MD, PhDCarlos E. B. Couri, MD, PhDAna B. P. L. Stracieri, MD, PhDMaria C. Oliveira, MD, MScDaniela A. Moraes, MDFabiano Pieroni, MD, PhDMarina Coutinho, MD, MScKelen C. R. Malmegrim, PhDMaria C. Foss-Freitas, MD, PhDBelinda P. Simo˜ es, MD, PhDMilton C. Foss, MD, PhDElizabeth Squiers, MDRichard K. Burt, MDTYPE 1 DIABETES MELLITUS (DM)results from a cell-mediated au-toimmune attack against pan-creatic beta cells.1The courseof autodestruction is subclinical untilthe amount of beta-cell mass is insuf-ficient to maintain glucose homeosta-sis. Thus, at the time of clinical diag-nosis, approximately 60% to 80% of thebeta-cell mass has been destroyed.2Type 1 DM comprises only 5% to10% of all diabetic etiologies but is as-sociated with a high frequency of vas-cular complications and compromisesquality and expectancy of life.3,4Pa-tients with type 1 DM depend on ex-ogenous insulin administration for sur-vival and for control of long-termcomplications. The best-establishedtreatment is tight control of blood glu-cose achieved by frequent daily injec-tions or continuous subcutaneous in-For editorial comment see p 1599.Author Affiliations: Department of Clinical Medicine,School of Medicine of Ribeira˜ o Preto, University of Sa˜oPaulo, Ribeira˜ o Preto, Brazil (Drs Voltarelli, Couri, Stra-cieri, Oliveira, Moraes, Pieroni, Coutinho, Malmegrim,Foss-Freitas, Simo˜ es, and Foss); Y’s Therapeutic Inc, Bur-lingame, Calif (Dr Squiers); and Division of Immuno-therapy, Northwestern University, Chicago, Ill (Dr Burt).Corresponding Author: Julio C. Voltarelli, MD, PhD, Re-gional Blood Center (Hemocentro), Campus USP, 14051-140 Ribeira˜ o Preto, Brazil ([email protected]).Context Type 1 diabetes mellitus (DM) results from a cell-mediated autoimmuneattack against pancreatic beta cells. Previous animal and clinical studies suggest thatmoderate immunosuppression in newly diagnosed type 1 DM can prevent further lossof insulin production and can reduce insulin needs.Objective To determine the safety and metabolic effects of high-dose immunosup-pression followed by autologous nonmyeloablative hematopoietic stem cell transplan-tation (AHST) in newly diagnosed type 1 DM.Design, Setting, and Participants A prospective phase 1/2 study of 15 patientswith type 1 DM (aged 14-31 years) diagnosed within the previous 6 weeks by clinicalfindings and hyperglycemia and confirmed with positive antibodies against glutamic aciddecarboxylase. Enrollment was November 2003-July 2006 with observation until Feb-ruary 2007 at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeira˜oPreto, Ribeira˜ o Preto, Brazil. Patients with previous diabetic ketoacidosis were excludedafter the first patient with diabetic ketoacidosis failed to benefit from AHST. Hematopoi-etic stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (10 µg/kg per day) and then collected from peripheral blood by leu-kapheresis and cryopreserved. The cells were injected intravenously after conditioningwith cyclophosphamide (200 mg/kg) and rabbit antithymocyte globulin (4.5 mg/kg).Main Outcome Measures Morbidity and mortality from transplantation and tem-poral changes in exogenous insulin requirements (daily dose and duration of usage).Secondary end points: serum levels of hemoglobin A1c, C-peptide levels during themixed-meal tolerance test, and anti–glutamic acid decarboxylase antibody titers mea-sured before and at different times following AHST.Results During a 7- to 36-month follow-up (mean 18.8), 14 patients became insulin-free (1 for 35 months, 4 for at least 21 months, 7 for at least 6 months; and 2 with lateresponse were insulin-free for 1 and 5 months, respectively). Among those, 1 patient re-sumed insulin use 1 year after AHST. At 6 months after AHST, mean total area under theC-peptide response curve was significantly greater than the pretreatment values, and at12 and 24 months it did not change. Anti–glutamic acid decarboxylase antibody levelsdecreased after 6 months and stabilized at 12 and 24 months. Serum levels of hemoglo-bin A1cwere maintained at less than 7% in 13 of 14 patients. The only acute severe ad-verse effect was culture-negative bilateral pneumonia in 1 patient and late endocrine dys-function (hypothyroidism or hypogonadism) in 2 others. There was no mortality.Conclusions High-dose immunosuppression and AHST were performed with ac-ceptable toxicity in a small number of patients with newly diagnosed type 1 DM. WithAHST, beta cell function was increased in all but 1 patient and induced prolonged in-sulin independence in the majority of the patients.Trial Registration clinicaltrials.gov Identifier: NCT00315133JAMA. 2007;297:1568-1576 www.jama.com1568 JAMA, April 11, 2007—Vol 297, No. 14 (Reprinted) ©2007 American Medical Association. All rights reserved. at STANFORD Univ Med Center, on November 10, 2007 www.jama.comDownloaded fromfusion of insulin, ie, intensive insulintherapy. This treatment reduces the riskof retinopathy, nephropathy, and neu-ropathy by 35% to 90% when com-pared with conventional therapy with1 to 2 injections per day.5Subgroup analysis of the DiabetesControl and Complications Trial showedthat patients with a larger beta cell re-serve demonstrable by serum C-peptide levels presented a slower de-cline of these levels during the study andexperienced fewer microvascular com-plications than patients with low or un-detectable C-peptide concentrations.Therefore, beta cell preservation is an-other important target in the manage-ment of type 1 DM and in the preven-tion of its related complications.6Many clinical trials have evaluatedthe role of immunointervention in pre-venting residual beta cell loss by block-ing the autoimmune response withprednisone,7azathioprine,8,9predni-sone plus azathioprine,10cyclospor-ine,11antibodies against CD3,12,13heatshock protein,14and rabbit antithymo-cyte globulin.15These therapies wereshown to induce a slower decline orsome improvement in C-peptide lev-els when compared with placebogroups. However, almost all patients re-quired exogenous insulin use.Since 1996, organ-threatening sys-temic lupus erythematosus16and otherautoimmune diseases17have been suc-cessfully treated with high-dose immu-nosuppression followed by autolo-gous nonmyeloablative


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Stanford BIOC 230 - Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus

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