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Chronic granulomatous disease treatment options

CHRONIC GRANULOMATOUS DISEASE
TREATMENT OPTIONS
CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
THERAPY
Prevention of infection
Antibiotic, antimycotic and Interferon-gamma (IFNγ) prophylaxis Treatment of Acute infections
Treatment of inflamatory complications

Corticoesteroides (low dose prednisolone) Curative

CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
ANTIBIOTIC
Trimethoprim/sulfamethoxazole (co-trimoxazole) – 1990
Graam- bacteria (Serratia and Burkholderia spp) and Staphlylococci prevents colonization by resistant strains reduction of serious bacterial infections, surgical interventions and Seger, RA. Modern management of chronic granulomatous disease. British J Haematol. 2008;140:255-266 Margolis et al. Trimethroprim/sulfamethoxazole prophylaxis in the manegement of chronic granulomatous disease. J InfecDis.1990:162:723-6 CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
ANTIMYCOTIC
Itraconazole

high activity against Aspergillus spp intracellular activity (taken-up by neutrophils) reduction to 1/3 in the rate of Aspergillus infections Gallin et al, 2003(3) (randomized, double-blind, placebo controlled)• highly effective in preventing both serious and superficial fungal infections Seger, RA. Modern management of chronic granulomatous disease. British J Haematol. 2008;140:255-266 (3) Itraconazole to Prevent Fungal Infecions in Chronic Granulomatous Disease. Gallin et al. N Engl J Med.2003;384:2416-22 CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
Itraconazole to Prevent Fungal Infections in Chronic Granulomatous
Disease. Gallin et al
. N Engl J Med.2003;384:2416-22
139 patients: 61 courses of itraconazole and 63 courses of placebo 1 itraconazole vs 7 placebo (p=0,10) 0 itraconazole vs 5 placebo (p=0,006) * Invasive infection of the lung, bone, blood, or soft tissue, with positive histological studies or culture CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
INTERFERON-GAMMA (IFNγ)
Improves splicing efficiency leading to generation of a small amount of increase in cytocrome b expression, allowing near normal levels of O2- production and bactericidal activity of neutrophils and monocytes DOES NOT reverse the defect in superoxide production Reduction of serious bacterial infections?? (1) Seger, RA. Modern management of chronic granulomatous disease. British J Haematol. 2008;140:255-266 CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
IFNγ – CONTROVERSY
The International CGD Cooperative Study Group,1991
Multicenter, transatlantic, randomized, double-blind, placebo-controlled phase III study (128 patients with classical CGD) 70% reduction in the frequency of severe infections Clinical improvements were NOT accompanied by NADPH oxidase function improvements NO significant efficacy in preventing Aspergillus infections Cost, subcutaneous administration, side effects (1) Seger, RA. Modern management of chronic granulomatous disease. British J Haematol. 2008;140:255-266 CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
IFNγ – CONTROVERSY
Prophylaxis is offered only in selected cases (UK 35% of patients)(4) United States
Universally prescribed (US 79% of patients)(4) (4) Jones et al. Chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry.
Clin and Exp Immunol. 2008;152:211-218 CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
IFNγ – Europe
Clinical features, long term follow-up and outcome of a large cohort of
patients with CGD: An Italian multicenter study. Clin Immunol.2008;126:155-164
Retrospective and immunological survey (60 patients) Prospective controlled non-randomized study of the efficacy of long-term IFNγ IFNγ DID NOT significantly change the rate of total and severe infections CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
IFNγ – Europe
Italian multicenter study
*Infection rate per patient-year: nº infections/nº of years of observation/nº patients CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
IFNγ – Europe
Jones et al. Chronic granulomatous disease in the United Kingdom and Ireland:
A comprehensive national patient-based registry. Clin and Exp Immunol.
2008;152:211-218
2 patients (2%) received IFNγ as continuous prophylaxis 33 patients (35%) received IFNγ during infective episodes no evaluation of bacterial infections per patient-year in either group CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
PROPHYLAXIS
IFNγ – United States
Marciano et al. Long term IFNγ Therapy for patients with Chronic
Granulomatous Disease. Clin Infect Diseases.2004;39:692-9
monitor the safety and efficacy of long term IFNγ treatment 98 serious infections during the study period 0.10 proven bacterial infections per patient-year interruption of IFNγ due to adverse events in 10 patients (13%) (reinitiated CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
HAEMOPOIETIC STEM CELL (HSC) TRANSPLANTATION(1)
conventional myeloablative marrow conditioning followed by transplantation of normal unmodified HSC subablative reduced-intensity conditioning (RIC) nonmyeloablative conditioning followed by T-cell-depleted HLA-genoidentical HSC transplant (1) Seger, RA. Modern management of chronic granulomatous disease. British J Haematol. 2008;140:255-266 CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
HSC TRANSPLANTATION – INDICATIONS(1)
Standard risk patient
High risk patient
(absent infection/inflammation)
(ongoing infection/inflammation)
≥1 life-threatening infection in the past Non-compliance with antibiotic prophylaxis (1) Seger, RA. Modern management of chronic granulomatous disease. British J Haematol. 2008;140:255-266 CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
Seger et al. Treatment of chronic granulomatous disease with
myeloablative conditioning and an unmodified hemopoietic allograft: a
survey of the European experience, 1985-2000. Blood.2002;100:4344-4350
27 patients (25 children / 2 adults); 6 years follow up, 14 centres myeloablative marrow conditioning (23/27)* unmodified hemopoeitic allograft from HLA-identical donor (25 from identical ** low-dose Bu(8mg/Kg) or low dose total body irradiation (200cCy) / Patients with active infection/inflammation CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
Seger et al. Treatment of chronic granulomatous disease with
myeloablative conditioning and an unmodified hemopoietic allograft: a
survey of the European experience, 1985-2000. Blood.2002;100:4344-4350
cure in 22/23 (81%) with full donor-derived hemopoietic chimerism* clearance of pre-exiting infection and inflammatory lesions CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
Seger et al. Treatment of chronic granulomatous disease with
myeloablative conditioning and an unmodified hemopoietic allograft:
a survey of the European experience, 1985-2000. Blood.2002;100:4344-4350
Acute severe GVHD (grade 3 or 4) in 4/27 patients (2 died) Exacerbation of Aspergillus infection during aplasia (N=3) Inflammatory flare at infection site during neutrophil engraftment (N=2) * All 9 patients (GVHD + AE) had pre-existing infection or inflammatory disease CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
Subablative reduced-intensity conditioning (RIC)
Bu 8m/kg, fludarabine 180mg/m2 and ATG 40mg/kg) Full donor chimerism and cure in all cases 4Cy total body irradiation, cyclophosphamide 50mg/Kg and fludarabine 200mg/m2, followed by a two HLA-mismatched cord blood transplantation one adult with McLeod phenotype CGD and invasive aspergillosis (1) Seger, RA. Modern management of chronic granulomatous disease. British J Haematol. 2008;140:255-266 CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
Horwitz Me et al. Treatment of chronic granulomatous disease with
nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft.
N Engl J Med
.2001;344:881-888
10 patients (5 adults / 5 children), follow up of 17 months all patients free of infections at transplantation peripheral-blood stem cell transplantation from HLA identical sibling 9/10 patients received donor-lymphocyte infusions (DLIs) to improve donorchimerism *Cy 60mg/Kg (days 7 and 6 before transp) + fludarabine 25mg(m2 (days 5-1 before transp) + ATG 40mg/Kg (days 5-2 before transp) CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
Horwitz Me et al. Treatment of chronic granulomatous disease with
nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft.
N Engl J Med.2001;344:881-888
8/10 patients 33-100% donor neutrophils in circulation 6/10 patients with 100% donor chimerism (4 adults / 2 children) preexisting granulomatous lesions resolved in patients with sucessful transplantation CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
Horwitz Me et al. Treatment of chronic granulomatous disease with
nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft.
N Engl J Med.2001;344:881-888
Acute GVHD grade II,III,IV in 3/10 patients (adults) CHRONIC GRANULOMATOUS DISEASE – TREATMENT OPTIONS
CURE OF THE DISEASE
HSC TRANSPLANTATION - RESUME
Conventional myeloablative conditioning + transplantation unmodified HSC 85% patients with full and stable engraftment of donor-derived hemopoiesis after a median of 18.5 days Subablative reduced-intensity conditioning (RIC) promising treatment for fragile patients with intractable infection or inflammation Nonmyeloablative conditioning + T-cell-depleted HSC transplant necessary DLIs for a more favorable donor chimerism

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