Allogeneic Stem Cell Transplantation Using Myeloablative and Reduced-Intensity Conditioning in Patients with Major Histocompatibility Complex Class II Deficiency
2010; Elsevier BV; Volume: 16; Issue: 6 Linguagem: Inglês
10.1016/j.bbmt.2010.01.002
ISSN1523-6536
AutoresHamoud Al‐Mousa, Zamil Al-Shammari, Abdulaziz Al‐Ghonaium, Hasan Al‐Dhekri, Saleh Al‐Muhsen, Bander Al-Saud, Rand Arnaout, Amal Al-Seraihy, Abdullah Al‐Jefri, Ali Alahmari, Mouhab Ayas, Hassan El‐Solh,
Tópico(s)Immune Cell Function and Interaction
ResumoMajor histocompatibility complex class II (MHC II) deficiency is a rare combined immunodeficiency disease. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Between June 1994 and February 2007, 30 children with MHC II deficiency underwent a total of 33 HSCT procedures. Median age at HSCT was 27 months. The stem cell source was unmanipulated bone marrow from HLA-identical related donors in 26 patients, one HLA antigen-mismatched bone marrow in 3 patients, and unrelated umbilical cord blood in 1 patient. Conditioning was with one of 3 myeloablative regimens—regimen A (18 patients): busulfan (Bu), cyclophosphamide (Cy), and etoposide; regimen B (2 patients): Bu, Cy, and antithymocyte globulin (ATG); or regimen C (1 patient): CY and total body irradiation (TBI)—or with a reduced-intensity regimen (12 patients): fludarabine, melphalan, and ATG. The median CD34 cell dose was 8.3 × 106/kg. Twenty patients experienced immune reconstitution and had sustained engraftment ranging from 9% to 100% for lymphoid lines and from 5% to 100% for myeloid lines that were significant to cure the disease. The overall disease-free survival rate was 66% and 76% after HLA-identical HSCT, with a median follow-up of 6.3 years, which is higher than previously reported. In HLA-identical transplant recipients, reliable donor stem cell engraftment and immune reconstitution were achieved through myeloablative or reduced-intensity conditioning. Further studies and long-term follow-up are needed to determine the appropriate conditioning regimen. Major histocompatibility complex class II (MHC II) deficiency is a rare combined immunodeficiency disease. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Between June 1994 and February 2007, 30 children with MHC II deficiency underwent a total of 33 HSCT procedures. Median age at HSCT was 27 months. The stem cell source was unmanipulated bone marrow from HLA-identical related donors in 26 patients, one HLA antigen-mismatched bone marrow in 3 patients, and unrelated umbilical cord blood in 1 patient. Conditioning was with one of 3 myeloablative regimens—regimen A (18 patients): busulfan (Bu), cyclophosphamide (Cy), and etoposide; regimen B (2 patients): Bu, Cy, and antithymocyte globulin (ATG); or regimen C (1 patient): CY and total body irradiation (TBI)—or with a reduced-intensity regimen (12 patients): fludarabine, melphalan, and ATG. The median CD34 cell dose was 8.3 × 106/kg. Twenty patients experienced immune reconstitution and had sustained engraftment ranging from 9% to 100% for lymphoid lines and from 5% to 100% for myeloid lines that were significant to cure the disease. The overall disease-free survival rate was 66% and 76% after HLA-identical HSCT, with a median follow-up of 6.3 years, which is higher than previously reported. In HLA-identical transplant recipients, reliable donor stem cell engraftment and immune reconstitution were achieved through myeloablative or reduced-intensity conditioning. Further studies and long-term follow-up are needed to determine the appropriate conditioning regimen. IntroductionMajor histocompatibility complex class II (MHC II) deficiency is a rare combined immunodeficiency disease characterized by profoundly deficient human leukocyte antigen (HLA) class II expression and lack of cellular and humoral immune responses to foreign antigens. The disease is also referred to as bare lymphocyte syndrome type II. Clinical manifestations include extreme susceptibility to viral, bacterial, fungal, and protozoal infections, primarily of the respiratory and gastrointestinal tract. Severe malabsorption with failure to thrive ensues, often leading to death in early childhood [1Griscelli C. Lisowska-Grospierre B. Mach B. Combined immunodeficiency with defective expression of MHC class П genes.Immunodef Rev. 1989; 1: 135-153PubMed Google Scholar, 2Klein C. Lisowska-Grospierre B. LeDeist F. et al.Major histocompatibility complex class П deficiency: clinical manifestations, immunological features and outcome.J Pediatr. 1993; 123: 921-928Abstract Full Text PDF PubMed Scopus (165) Google Scholar, 3Saleem M.A. Arkwright P.D. Davies E.G. et al.Clinical course of patients with major histocompatibility complex class П deficiency.Arch Dis Child. 2000; 83: 356-359Crossref PubMed Scopus (49) Google Scholar, 4Villard J. Masternak K. Lisowska-Grospierre B. et al.MHC class II deficiency: a disease of gene regulation.Medicine. 2001; 80: 405-418Crossref PubMed Scopus (50) Google Scholar].The disease is an autosomal recessive disease resulting from defects in several distinct transacting regulatory factors required for the expression of MHC II genes. This deficiency is classified into 4 complementation groups. Mutations in CIITA (complementation group A), RFXANK (complementation group B), RFX5 (complementation group C), and RFXAP (complementation group D) have been identified in individuals with MHC II deficiency [4Villard J. Masternak K. Lisowska-Grospierre B. et al.MHC class II deficiency: a disease of gene regulation.Medicine. 2001; 80: 405-418Crossref PubMed Scopus (50) Google Scholar].Allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only available curative treatment for MHC II deficiency. HSCT can cure the disease, provided that it is performed before the development of complications leading to severe organ failure [5Klein C. Cavazzana-Calvo M. Le Deist F. et al.Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients.Blood. 1995; 85: 580-587PubMed Google Scholar, 6Antoine C. Muller Cant A. Muller S. Cant A. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of European experience 1968–99.Lancet. 2003; 361: 553-560Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar]. In the European registry data, HSCT in patients with MHC class II deficiency was associated with a lower survival rate than HSCT performed for other primary immunodeficiencies [6Antoine C. Muller Cant A. Muller S. Cant A. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of European experience 1968–99.Lancet. 2003; 361: 553-560Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar, 7Buckley R.H. Fischer A. Bone marrow transplantation for primary immunodeficiency diseases.in: Ochs H.D. Smith C.E. Puck J.M. Primary Immunodeficiency Disease. Oxford University Press, Oxford, UK1999: 459-475Google Scholar]. These differences were observed for HSCT performed with matched and nonmatched donors alike, and MHC class II immunodeficiency seemed to carry a poor prognosis, especially after HLA nonidentical transplantation, with only 32% of patients surviving to 1 year [6Antoine C. Muller Cant A. Muller S. Cant A. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of European experience 1968–99.Lancet. 2003; 361: 553-560Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar]. The low survival after HLA-identical HSCT (53%) was likely related to the incidence of preexisting viral infections and was associated with a high incidence of acute graft-versus-host disease (aGVHD) [8Renella R. Picard C. Neven B. et al.Human leucocyte antigen–identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and preexisting viral infections.Br J Haematol. 2006; 134: 510-516Crossref PubMed Scopus (34) Google Scholar]. An interesting observation in long-term transplantation survivors is the persistence of a relative CD4 T cell lymphopenia, possibly because of a lack of HLA class II molecules on thymic epithelial cells [5Klein C. Cavazzana-Calvo M. Le Deist F. et al.Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients.Blood. 1995; 85: 580-587PubMed Google Scholar].Given the available HSCT protocols for children with MHC II deficiency, intensive pretransplantation conditioning appears to be a prerequisite for reliable engraftment and complete immune reconstitution. But, this conditioning is associated with an increased risk of short-term and long-term toxicity, particularly infections and end-organ decompensation, leading to a high rate of treatment-related mortality, especially in older children who acquire organ dysfunction. Late adverse effects, including growth retardation, infertility, and secondary malignancies, also are of concern.Driven by concerns about myeloablative (MA) regimens, some groups have reported success using reduced-intensity conditioning (RIC) regimens in patients with hematologic malignancies [9Giralt S. Estey E. Albitar M. et al.Engraftment of allogeneic hematopoietic progenitor cells with purine analog–containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy.Blood. 1997; 89: 4531-4536PubMed Google Scholar, 10Slavin S. Nagler A. Naparstek E. et al.Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases.Blood. 1998; 91: 756-763PubMed Google Scholar, 11Childs R. Clave E. Contentin N. et al.Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses.Blood. 1999; 94: 3234-3241PubMed Google Scholar]. Recent reports of RIC regimen-based HSCT in patients with primary immunodeficiencies and significant organ dysfunction indicated good engraftment and immune reconstitution with minimal toxicity and GVHD [12Amrolia P. Gaspar H.B. Hassan A. et al.Nonmyeloablative stem cell transplantation for congenital immunodeficiencies.Blood. 2000; 96: 1239-1246PubMed Google Scholar]. In one series, high-risk patients treated with RIC-based HSCT had better survival than those treated with MA HSCT (94% vs 53%) [13Rao K. Amrolia P.J. Jones A. et al.Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen.Blood. 2005; 105: 879-885Crossref PubMed Scopus (192) Google Scholar]. Here we describe the outcomes of a large series of patients with MHC II deficiency who underwent HSCT at a single center using MA conditioning and RIC.Patients and MethodsPatient CharacteristicsBetween June 1994 and February 2007, 30 children with MHC II deficiency underwent 33 HSCT procedures at King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh, Saudia Arabia. Three patients required a second HSCT trial. A retrospective chart review was conducted with multivariate factors including pre-HSCT clinical and immunologic characteristics, HSCT characteristics (ie, age at HSCT; donor status including age, sex, and HLA match; serologic status; conditioning regimen; toxicity; stem cell origin; CD34+ cells dose infused; bone marrow manipulation; engraftment; GVHD; infections; and outcome), and immune reconstitution post-HSCT at last follow-up. The diagnosis was made through the analysis of MHC-II expression on peripheral blood monocytes, B cells, and activated T cells. Assessment of isolated pathogens was made through culture or polymerase chain reaction (PCR) of material obtained by specimen collection or biopsy. The study was approved by KFSHRC's Institutional Review Board.Preparative Regimen, Transplantation, and Supportive CareConditioning therapy consisted of one of 3 MA regimens—regimen A (18 patients): busulfan (Bu) 16 mg/kg (days -10 to -7), cyclophosphamide (Cy) 200 mg/kg (days -5 to -2), and etoposide (VP-16) 300 mg/m2/day (days -5 to -3), regimen B (2 patients): Bu, Cy, and antithymocyte globulin (ATG) 5 mg/kg/day (days -5 to -2), or regimen C (1 patient): Cy and total body irradiation (TBI)—or a RIC regimen (12 patients) comprising fludarabine 30 mg/m2 /day (days -7 to -3), melphalan 140 mg/m2 (day -2), and ATG 5 mg/kg/day (days -2 to +2). The stem cell sources were unmanipulated bone marrow from HLA-genoidentical siblings in 19 patients, HLA-phenotypically identical related donors in 7 patients, one antigen HLA-mismatched related donors in 3 patients, and unrelated umbilical cord blood in 1 patient. HLA-compatibility was assessed serologically at class 1 (A, B, and C loci) and molecularly at class 2 (DRB1 and DQB1 loci). The total number of CD34+ stem cells infused on the day of transplantation ranged from 3 to 20.7 × 106/kg (median, 8.7 × 106/kg). GVHD prophylaxis consisted of cyclosporine (CsA) and methotrexate (MTX) in 17 patients, CsA alone in 15 patients, and CsA and a steroid in 1 patient. All patients were placed in a positive-pressure isolation room. Febrile illnesses during periods of aplasia were treated with standard preemptive intravenous antibiotherapy. Hematologic support with matched erythrocytes and platelets was provided where indicated. All blood products were irradiated and were cytomegalovirus (CMV)-negative for CMV-negative patients. Detection of CMV in the donor or the recipient before transplantation led to preemptive treatment with intravenous acyclovir (1500 mg/m2/day) for 60 days. All patients received granulocyte colony-stimulating factor 5 μg/kg per day from day +8 until absolute neutrophil count (ANC) recovered to >0.5 × 109/L. Intravenous immunoglobulin was administered once every 3 weeks.Assessment of Engraftment and GVHDEngraftment was confirmed by the presence of MHC-II expression on peripheral blood monocytes, B lymphocytes, and activated T lymphocytes. Chimerism was tested by short tandem repeat typing. Phenotyping of circulating peripheral blood mononuclear cells was performed by 3-color immunofluorescence with flow cytometry using monoclonal antibodies specific for CD3, CD4, CD8, and CD19. T cell function was determined in vitro by proliferative responsiveness to phytohemagglutinin and tetanus toxoid stimulation. Serum Ig level was measured by nephelometry.The diagnosis of aGVHD and/or chronic GVHD (cGVHD) was made according to the established consensus criteria for GVHD grading [14Przepiorka D. Weisdorf D. Martin P. et al.1994 Consensus Conference on Acute GVHD Grading.Bone Marrow Transplant. 1995; 15: 825-828PubMed Google Scholar] and confirmed when necessary by biopsy and pathological analysis. All patients were treated with corticosteroids and received additional immunomodulatory therapy as needed.ResultsPretransplantation Clinical and Immunologic CharacteristicsPretransplantation clinical and immunologic characteristics are summarized in Table 1, Table 2. The study group comprised 19 males and 11 females, with a median age at diagnosis of 16 months (range, 1 week to 114 months). Recurrent chest infections, chronic diarrhea, and failure to thrive were the most common clinical manifestations. Most patients had evidence of an active infection or a pathogen, including CMV (n = 7), Epstein-Barr virus (EBV) (n = 2), Pneumocystis jiroveci (n = 3), enterovirus (n = 2), and cryptosporidiosis (n = 2). MHC II expression was absent on B cells and activated T cells in all patients, and variable hypogammaglobulinemia was seen. Three patients were diagnosed on newborn screening because of a family history of MHC II deficiency. The median age at HSCT was 27 months (range, 1-120 months).Table 1Clinical and Immunologic Characteristics Pre-HSCTCharacteristicValueNormal RangeAge, mean (range)16 months (1 week to 114 months)Sex19 M/11 F-Chest infections, n∗Patients positive/total patients.27/30-Protracted diarrhea, n∗Patients positive/total patients.26/30-Hepatitis/cholangitis, n∗Patients positive/total patients.4/30-CMV, n∗Patients positive/total patients.7/30-Pneumocystis jiroveci pneumonia, n∗Patients positive/total patients.3/30-EBV, n∗Patients positive/total patients.2/30-Enterovirus, n∗Patients positive/total patients.2/30-Cryptosporidiosis, n∗Patients positive/total patients.2/30-IgG, g/L, range (median)1.4-16.4 (4.7)3.5-12.4CD3 cells/mm3, range (median)470-5294 (2461)2200-4100CD4 cells/mm3, range (median)118-2106 (946)1400-2800CD19 cells/mm3, range (median)100-1716 (951)700-1600MHC II expression (% positive cells)†MHC II expression was evaluated on B cells (B) and activated T cells (act)< 1%-Lymphocyte response to phytohemagglutinin, cpm, range (median)9022-270,063 (85,565)94,935-171,149Lymphocyte response to tetanus texoid, cpm, range (median)169-350 (224)6790-54,368HSCT indicates hematopoietic stem cell transplantation; CMV, cytomegalovirus; EBV, Epstein-Barr virus; MHC, major histocompatibility complex.∗ Patients positive/total patients.† MHC II expression was evaluated on B cells (B) and activated T cells (act) Open table in a new tab Table 2Stem Cell Transplantation CharacteristicsMyeloablativeRICAge at HSCT, months, range (median)1-44 (14.4)2-120 (43.3)HLA match, n10/10 S, 1410/10 S, 310/10 R, 510/10 R, 58/10 UC, 19/10 R, 3CD34 dose/kg, range (median)3-20.7 × 106 (9.3)4.1-11 × 106 (7.7)Stem cell sourceBone marrowBone marrowGVHD, n AcuteSkin, 9Skin, 7Gut, 5Lung, 1 ChronicSkin, 3Gut, 2ANC >500, days, range (median)10-43 (17.6)11-16 (13)Platelets > 20 × 109/L, days, range (median)11-78 (25.2)15-85 (28.7)Veno-occlusive disease, n1-Hepatotoxicity, n2-CMV, n62Mortality, n31HSCT indicates hematopoietic stem cell transplantation; GVHD, graft-versus-host disease; ANC, absolute neutrophil count; CMV, cytomegalovirus; RIC, reduced-intensity conditioning; S, sibling; R, related; UC, unrelated umbilical.HLA identity is based on HLA-A, -B, -C, -DR, and -DQ determination. Open table in a new tab Survival and ToxicityTransplantation-related complications are summarized in Table 2. Suspected veno-occlusive liver disease (n = 1) and significant hepatotoxicity (n = 2) were seen in the MA group. With regard to infections, all patients experienced more than one episode of neutropenic fever that was treated with standard preemptive intravenous antibiotherapy and adjusted according to culture results. CMV reactivation occurred in 8 patients (6 with MA conditioning and 2 with RIC) and was treated with anti-CMV therapy. Suspected fungal sinus infections were observed in 5 patients. Four patients died, including 3 patients in the MA group (2 after second HSCT and 1 after unrelated umbilical cord blood transplant) secondary to chemotherapy-related toxicity, sepsis, and multiorgan failure and 1 patient in the RIC group secondary to bacterial sepsis.The overall disease-free survival was 66% (20/30) and 76% (20/26) after HLA-identical HSCT, with a median follow-up of 6.3 years which is higher than previously reported [8Renella R. Picard C. Neven B. et al.Human leucocyte antigen–identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and preexisting viral infections.Br J Haematol. 2006; 134: 510-516Crossref PubMed Scopus (34) Google Scholar] (Figure 1). No significant differences in disease free-survival after HLA-identical HSCT based on conditioning regimen (MA or RIC) or age at HSCT ( 1 year) were seen. All 3 patients who underwent HSCT from a one antigen-mismatched donor using an RIC regimen rejected their grafts despite primary engraftment. Two of the 3 patients who were diagnosed early in life because of family history of the disease and underwent preemptive HSCT before the development of symptomatic infections rejected their grafts, and 1 of them died after a second HSCT.EngraftmentThe median time to neutrophil recovery to ANC >0.5 × 109/L was 17.6 days (range, 10-43 days) for the MA group and 13 days (range, 11-16 days) for the RIC group. The median time to an unsupported platelet count of >20 × 109/L was 25.2 days (range, 11 to 78 days) for the MA group and 28.7 days (range, 15-85 days) for the RIC group (Table 2). Our chimerism data demonstrate that 20 patients had sustained mixed hematopoietic chimerism, with donor lymphocyte cell chimerism ranging from 9% to 100% and donor myeloid cell chimerism ranging from 5% to 100%. The median lymphocyte cell and myeloid cell chimerism were 68% and 63%, respectively, with a median follow-up of 79 months in the MA group, and 42% and 22% with a median of follow-up of 35 months in the RIC group.GVHDVariable degrees of aGVHD were seen in the myeloablative group involving skin (n = 9; grade II-III), gut (n = 5; grade II-III), and lung (n = 1). Three patients developed cGVHD (n = 2 skin and gut; n = 1 skin). Seven patients in the RIC group developed grade I-II acute skin aGVHD with no other organ involvement that responded well to standard steroid therapy. No patient developed cGVHD.Immune ReconstitutionTwenty patients (66%) (76% post HLA-identical HSCT) has sustained engraftment and immune reconstitution. Immune reconstitution in the MA and RIC groups are summarized in Table 3. Patients achieved normal lymphocyte counts by 3-6 months post-HSCT. Variable CD4 lymphopenia was observed, with a median value of 617 cells/mm3. T cell reconstitution was confirmed in all patients through the establishment of MHC II expression on activated T cells. Lymphocyte proliferation to mitogens normalized, whereas response to antigens improved but remained subnormal in both groups. Despite variable donor B cell engraftment, B cell counts returned to normal within weeks or months. IgG level normalized in all patients, and intravenous immunoglobulin therapy was discontinued. All patients mounted a protective antibody response by 6 weeks postvaccination to 3 doses of tetanus vaccine (representative of protein antigen) and 1 dose of unconjugated pneumococcal (polysaccharide) vaccine.Table 3Immune Reconstitution on Last Follow-UpMyeloablativeRICNormal RangeTime post-HSCT, months, range (median)44-122 (79)25-44 (35)-Chimerism, %, range (median) Lymphocytes9%-100% (68%)14%-84% (42%)- Myeloid5%-100% (63%)10%-45% (22%) CD3 cells/mm3, range (median)986-4888 (2212)1423-2253 (1752)2200-4100CD4 cells/mm3, range (median)315-1183 (662)294-914 (564)1400-2800Total MHC II, range (median)∗Absolute number of MHC II+ cells/mm3, including B cells and activated T cells.79-1544 (651)165-2427 (714)-CD19 cells/mm3 (median)96-1125 (514)110-812 (620)700-1600MHC II/CD19, range (median)32-1029 (349)37-218 (104)700-1600IgG, g/L, range (median)6.2-14.5 (10.4)6.6-17.3 (10.7)3.5-12.4Protective antibody response to tetanus, n13/13†Patients positive/total patients.7/7†Patients positive/total patients.-Protective antibody response to unconjugated pneumococcal vaccine, n13/13†Patients positive/total patients.7/7†Patients positive/total patients.-Phytohemagglutinin, cpm, range (median)36,460-190,362 (82,543)59,193-162,217 (112,113)94935-171,149Tetanus, cpm, range (median)269-11,262 (3249)1005-9476 (4226)6790-54,368HSCT indicates hematopoietic stem cell transplantation; MHC, major histocompatibility complex; RIC, reduced-intensity conditioning.∗ Absolute number of MHC II+ cells/mm3, including B cells and activated T cells.† Patients positive/total patients. Open table in a new tab Clinical Course and InfectionsAt the time of this report, 20 patients were alive and well. All patients were able to clear their chronic infections. None had developed a severe infection, and those patients with preexisting bronchiectasis and chronic lung disease demonstrated some clinical improvement, with mild intermittent chest exacerbations treated successfully with oral antibiotics.Second HSCTTwo patients who underwent a second HSCT using MA conditioning (Bu, Cy, and ATG, and Cy and TBI) died secondary to chemotherapy toxicity, sepsis, and multiorgan failure. One patient who underwent retransplantation 7 years after the first transplantation with a RIC regimen had sustained engraftment and immune reconstitution.DiscussionThe high rate of consanguinity in Saudi Arabia has resulted in an increased incidence of primary immunodeficiency disorders, including MHC II deficiency. Little is known about the molecular aspects of this disease in Saudi Arabia. MHC deficiency is seen predominantly in 2 Saudi tribes, and it will be of interest to study the underlying genetic defects in our patients to assess for a possible predominant mutation in this population and to explore whether the genotype has any effect on the outcome of HSCT.This study provides the largest series to date of patients with MHC II deficiency who underwent allogeneic HSCT at a single center. Patients who underwent HSCT with standard Bu/Cy conditioning regimens had higher donor cell engraftment, suggesting that this might be a reasonable standard regimen for HSCT in patients with MHC II deficiency. An RIC regimen may be particularly suited for patients with comorbid conditions, many of whom are referred for allogeneic HSCT when critically ill with a disseminated infection.HSCT using an RIC regimen was well tolerated and carried a lower incidence of infective complications and less-severe GVHD compared with HSCT with a standard Bu/Cy conditioning regimen. Even though this finding is encouraging, it is limited by the short follow-up; further studies are merited to follow our cases and assess the long-term stability of the grafts in both regimens.We found a 76% disease-free survival rate in our patients with MHC II deficiency who underwent HLA-identical related transplants, which is higher than reported previously [8Renella R. Picard C. Neven B. et al.Human leucocyte antigen–identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and preexisting viral infections.Br J Haematol. 2006; 134: 510-516Crossref PubMed Scopus (34) Google Scholar]. A significant incidence of mixed chimerism was seen in both the MA and RIC groups; however, it is well established that mixed chimerism is sufficient to cure the disease. Interestingly, CD4 T cell lymphopenia persisted after HSCT and was not influenced by the type of conditioning used, possibly reflecting impaired thymic maturation of CD4 T cells because of decreased MHC II expression in thymic epithelium. The fact that our patients were able to clear viral infections (CMV, EBV, rotavirus, and enterovirus) and cryptosporidiosis attests to a significant recovery of functional immunity. Despite variable donor B cell engraftment, all patients were able to produce normal IgG, IgA, and IgM levels by 6 months post-HSCT. The determination of in vivo specific antibody responses to immunization confirms the restoration of B cell function.In summary, we have demonstrated that reliable donor stem cell engraftment and immune reconstitution after HLA-identical HSCT can be achieved with either an MA conditioning regimen or an RIC regimen. RIC is associated with a high rate of rejection in mismatched transplants. A high mortality rate was seen after second HSCT. Further studies and long-term follow-up are needed to determine the appropriate conditioning regimen.AcknowledgmentsThe authors thank the patients and their families for their trust and cooperation, and the nurses and clinicians for the care of the patients.Financial disclosure: The authors have nothing to disclose.Authorship statementHamoud Al-Mousa provided patient care, designed the study, collected and analyzed data, and wrote the manuscript. Zamil Al-Shammari provided patient care and collected data. Abdulaziz Al-Ghonaium, Hasan Al-Dhekri, Saleh Al-Muhsen, Bander Al-Saud, Rand Arnaout, Amal Al-Seraihy, Abdullah Al-Jefri, Ali Al-Ahmari, Mouhab Ayas, and Hassan El-Solh provided patient care. IntroductionMajor histocompatibility complex class II (MHC II) deficiency is a rare combined immunodeficiency disease characterized by profoundly deficient human leukocyte antigen (HLA) class II expression and lack of cellular and humoral immune responses to foreign antigens. The disease is also referred to as bare lymphocyte syndrome type II. Clinical manifestations include extreme susceptibility to viral, bacterial, fungal, and protozoal infections, primarily of the respiratory and gastrointestinal tract. Severe malabsorption with failure to thrive ensues, often leading to death in early childhood [1Griscelli C. Lisowska-Grospierre B. Mach B. Combined immunodeficiency with defective expression of MHC class П genes.Immunodef Rev. 1989; 1: 135-153PubMed Google Scholar, 2Klein C. Lisowska-Grospierre B. LeDeist F. et al.Major histocompatibility complex class П deficiency: clinical manifestations, immunological features and outcome.J Pediatr. 1993; 123: 921-928Abstract Full Text PDF PubMed Scopus (165) Google Scholar, 3Saleem M.A. Arkwright P.D. Davies E.G. et al.Clinical course of patients with major histocompatibility complex class П deficiency.Arch Dis Child. 2000; 83: 356-359Crossref PubMed Scopus (49) Google Scholar, 4Villard J. Masternak K. Lisowska-Grospierre B. et al.MHC class II deficiency: a disease of gene regulation.Medicine. 2001; 80: 405-418Crossref PubMed Scopus (50) Google Scholar].The disease is an autosomal recessive disease resulting from defects in several distinct transacting regulatory factors required for the expression of MHC II genes. This deficiency is classified into 4 complementation groups. Mutations in CIITA (complementation group A), RFXANK (complementation group B), RFX5 (complementation group C), and RFXAP (complementation group D) have been identified in individuals with MHC II deficiency [4Villard J. Masternak K. Lisowska-Grospierre B. et al.MHC class II deficiency: a disease of gene regulation.Medicine. 2001; 80: 405-418Crossref PubMed Scopus (50) Google Scholar].Allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only available curative treatment for MHC II deficiency. HSCT can cure the disease, provided that it is performed before the development of complications leading to severe organ failure [5Klein C. Cavazzana-Calvo M. Le Deist F. et al.Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients.Blood. 1995; 85: 580-587PubMed Google Scholar, 6Antoine C. Muller Cant A. Muller S. Cant A. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of European experience 1968–99.Lancet. 2003; 361: 553-560Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar]. In the European registry data, HSCT in patients with MHC class II deficiency was associated with a lower survival rate than HSCT performed for other primary immunodeficiencies [6Antoine C. Muller Cant A. Muller S. Cant A. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of European experience 1968–99.Lancet. 2003; 361: 553-560Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar, 7Buckley R.H. Fischer A. Bone marrow transplantation for primary immunodeficiency diseases.in: Ochs H.D. Smith C.E. Puck J.M. Primary Immunodeficiency Disease. Oxford University Press, Oxford, UK1999: 459-475Google Scholar]. These differences were observed for HSCT performed with matched and nonmatched donors alike, and MHC class II immunodeficiency seemed to carry a poor prognosis, especially after HLA nonidentical transplantation, with only 32% of patients surviving to 1 year [6Antoine C. Muller Cant A. Muller S. Cant A. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of European experience 1968–99.Lancet. 2003; 361: 553-560Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar]. The low survival after HLA-identical HSCT (53%) was likely related to the incidence of preexisting viral infections and was associated with a high incidence of acute graft-versus-host disease (aGVHD) [8Renella R. Picard C. Neven B. et al.Human leucocyte antigen–identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and preexisting viral infections.Br J Haematol. 2006; 134: 510-516Crossref PubMed Scopus (34) Google Scholar]. An interesting observation in long-term transplantation survivors is the persistence of a relative CD4 T cell lymphopenia, possibly because of a lack of HLA class II molecules on thymic epithelial cells [5Klein C. Cavazzana-Calvo M. Le Deist F. et al.Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients.Blood. 1995; 85: 580-587PubMed Google Scholar].Given the available HSCT protocols for children with MHC II deficiency, intensive pretransplantation conditioning appears to be a prerequisite for reliable engraftment and complete immune reconstitution. But, this conditioning is associated with an increased risk of short-term and long-term toxicity, particularly infections and end-organ decompensation, leading to a high rate of treatment-related mortality, especially in older children who acquire organ dysfunction. Late adverse effects, including growth retardation, infertility, and secondary malignancies, also are of concern.Driven by concerns about myeloablative (MA) regimens, some groups have reported success using reduced-intensity conditioning (RIC) regimens in patients with hematologic malignancies [9Giralt S. Estey E. Albitar M. et al.Engraftment of allogeneic hematopoietic progenitor cells with purine analog–containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy.Blood. 1997; 89: 4531-4536PubMed Google Scholar, 10Slavin S. Nagler A. Naparstek E. et al.Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases.Blood. 1998; 91: 756-763PubMed Google Scholar, 11Childs R. Clave E. Contentin N. et al.Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses.Blood. 1999; 94: 3234-3241PubMed Google Scholar]. Recent reports of RIC regimen-based HSCT in patients with primary immunodeficiencies and significant organ dysfunction indicated good engraftment and immune reconstitution with minimal toxicity and GVHD [12Amrolia P. Gaspar H.B. Hassan A. et al.Nonmyeloablative stem cell transplantation for congenital immunodeficiencies.Blood. 2000; 96: 1239-1246PubMed Google Scholar]. In one series, high-risk patients treated with RIC-based HSCT had better survival than those treated with MA HSCT (94% vs 53%) [13Rao K. Amrolia P.J. Jones A. et al.Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen.Blood. 2005; 105: 879-885Crossref PubMed Scopus (192) Google Scholar]. Here we describe the outcomes of a large series of patients with MHC II deficiency who underwent HSCT at a single center using MA conditioning and RIC.
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