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Alternative Donor SCT for the Treatment of MHC Class II Deficiency

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Alternative Donor SCT for the Treatment of MHC Class II Deficiency Bone Marrow Transplantation (2013) 48, 226–232 & 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13 www.nature.com/bmt ORIGINAL ARTICLE Alternative donor SCT for the treatment of MHC Class II deficiency TN Small1, W Qasim2, W Friedrich3, R Chiesa2, JJ Bleesing4, A Scurlock5, P Veys2 and M Sparber-Sauer3 MHC Class II deficiency is a rare primary immunodeficiency disease characterized by absent HLA Class II expression resulting in CD4 lymphopenia, lack of Ag-specific responses and recurrent infection. Without successful allogeneic SCT, most children succumb to infection within the first decade of life. To date, alternative donor transplants for this disorder have been inferior to SCT for other forms of combined immunodeficiency disease due to an increased incidence of graft rejection, GVHD and death from infections generally acquired before haematopoietic cell transplantation. This study details the transplant outcome of 16 affected children consecutively transplanted at four centers since 1990, 8 of whom required mechanical ventilation pretransplant. Stem cells were derived from an HLA-mismatched family member (n ¼ 10), an HLA-matched unrelated adult donor (n ¼ 4), or an unrelated cord blood donor (n ¼ 2). Graft failure occurred in five children, all of whom underwent a second SCT. Six patients developed acute GVHD although no patient developed chronic GVHD after primary transplantation. CD4 T-cell reconstitution remained below the normal range for age, suggesting defective thymopoiesis after allo-SCT. Nonetheless, 69% of children survive without GVHD at a median follow-up of 5.7 years, indicating improved outcomes compared with previous studies. Bone Marrow Transplantation (2013) 48, 226–232; doi:10.1038/bmt.2012.140; published online 24 September 2012 Keywords: immunodeficiency; MHC Class II deficiency; transplantation INTRODUCTION rejection, and less than optimal CD4 T-cell reconstitution following MHC Class II deficiency, also known as Type II Bare Lymphocyte SCT in this condition. Syndrome, is a rare form of autosomal recessive combined 1–12 immunodeficiency disease currently curable only by allo-SCT. MATERIALS AND METHODS Patients with this disease possess normal MHC Class II genes, but Patient characteristics, preparative regimen, graft characteristics, have mutations within one of four transactivating genes that GVHD prophylaxis and supportive care control their expression (reviewed in Reith and Mach2 and Villard 3 Sixteen consecutive patients with MHC II Class deficiency were referred to et al. ). Over 85% of affected children have mutations in genes the University of Ulm (n ¼ 8), Great Ormond Street Hospital (n ¼ 4), encoding subunits of regulatory factor X (RFXANK, RFXAP or RFX5), Cincinnati Children’s Hospital Medical Center (n ¼ 2) and Memorial a protein complex that binds to the MHC Class II promoter and Sloan-Kettering Cancer Center (n ¼ 2) between 1990 and 2011 for SCT. activates transcription. The remaining patients have defects of the The demographics and clinical characteristics of the seven females and Class II transactivator, a factor that regulates constitutive and IFN-g nine males are shown in Table 1. All patients were diagnosed by upregulation of MHC Class II antigens (reviewed in Reith and the absence of MHC Class II expression on peripheral blood monocytes Mach2 and Villard et al.3). and B cells by flow cytometry. Patients 12 and 16 had mutations in the Patients with MHC Class II deficiency generally have severe CD4 RFXAP and RFXANK genes, respectively. Mutations in the other patients are unknown. Median age (range) at time of initial transplant was 1.6 (0.5–4) T-cell lymphopenia, hypogammaglobulinemia and lack Ag-specific years. All but one patient had X1 life-threatening infection before responses resulting in chronic diarrhea, recurrent viral, parasitic transplant, including pneumonia in 14 patients, 8 of whom required 1,4,5,7 and bacterial infections, and failure to thrive. Although recent mechanical ventilation before SCT. In addition to pneumonia, the reports of allo-SCT for this disease have shown improved survival majority of patients had infectious diarrhea and failure to thrive. Patient following HLA-matched related donor transplantation,8,9 for those 11 had two episodes of PCP pneumonia and 1 episode of ECHO virus patients lacking such a donor survival of p50% has been meningoencephalitis before SCT. Patient 15 had rubella viremia before reported.4,5,7–9 transplantation. The rarity of this disease challenges physicians making transplant decisions for affected children who lack a well-matched Stem cell donor and preparative regimen. Transplant donors were family donor. We have collected data for 16 consecutive patients HLA-Ag-mismatched family members (n ¼ 10), HLA-allele-matched (10/10) transplanted at four centers in Europe and North America since unrelated adult volunteer donors (n ¼ 4) or unrelated cord blood donors (n ¼ 2) (Table 2). HLA typing for cord blood units was defined by 1990 to characterize outcomes following alternative donor SCT for serological typing for HLA A and B antigens and high-resolution molecular this disorder. With 69% (11/16) overall survival at a median follow- typing for HLA DRb1. up of 5.6 years, our experience indicates improved outcomes after Seven patients received T-cell-depleted SCT, six of whom received BU such transplants, but we highlight notable difficulties with graft (X16 mg/kg over 4 days), combined with thiotepa and fludarabine (n ¼ 3), 1Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Great Ormand Street Hospital, London, UK; 3University Children’s Hospital, Ulm, Germany; 4Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA and 5Arkansas Children’s Hospital, Little Rock, AR, USA. Correspondence: Dr TN Small, Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. E-mail: [email protected] Received 15 March 2012; revised and accepted 26 June 2012; published online 24 September 2012 Alternative donor SCT TN Small et al 227 Table 1. Pre-HCT patient characteristics Patient Age Ethnicity Pretransplant infections Hx of Pre-HCT Pre-HCT B Pre-HCT T-cell no. (years)/ mechanical T cells/mL and NK proliferative sex ventilation cells/mL responses Pre-HCT 1a 4/M African PCP pneumonia Yes CD3: 3906 CD19: 160 PHA: nl American FTT, diarrhea CD4: 517 CD56: 172 MLC: nl CD8: 2929 NK: 100:1:nl 2 2/F Turkish Candida pneumonia Yes CD3: 1094 CD19: 880 PHA: 25–50% nl BCGitis, FTT CD4: 694 CD56: not Gastroenteritis (Enterovirus, CD8: 534 tested Rotavirus) 3 3/M Turkish Pneumonia (unspecified) No CD3: 1554 CD19: 627 PHA: nl Recurrent otitis, diarrhea, CD4: 600 CD56: 273 MLC: 50% nl FTT, UTI CD8: 764 4 0.5/F Italian PCP pneumonia Yes CD3: 1069 CD19: 732 PHA: 50% nl FTT CD4: 237 CD56: 59 MLC: nl CD8: 811 NK: 100:1:nl 5 0.8/F Greek Chlamydia pneumonia Yes CD3: 2486 CD19342 NK: 100:1:nl VZV infection CD4: 435 CD56: 186 CD8: 2020 6 0.5/F Turkish None No CD3: 2052 CD19: 142 PHA: 50–75% nl CD4: 1140 CD56: 456 MLC: nl CD8: 855 NK: 100:1: 11% 7 1/F Saudi PCP and CMV pneumonia No CD3: 1193 CD19: 1909 NK: 100:1: 11% Arabian FTT, diarrhea CD4: 443 CD56: 170 CD8: 579 8 1.5/F Turkish Adenovirus pneumonia Yes CD3: 2148 CD19: 3029 PHA: 50–75% nl CD4: 495 CD56: 165 MLC: nl CD8: 1487 9 3/M Turkish Pneumonia, bronchitis thrush, No CD3: 893 CD19: 85 NT otitis media, gonorrheal arthritis CD4: 110 CD56: 159 diarrhea, FTT CD8: 599 10 1/F Caucasian PCP and RSV pneumonia Yes CD3: 2040 CD19: 1350 PHA: o25% nl CD4: 620 CD56: 20 CD8 1310 11 3/M Caucasian PCP pneumonia x2 Yes CD3: 1152 CD19: 722 PHA: 25% nl Meningoencephalitis (ECHO virus) CD4: 497 CD56: 248 Diarrhea (Salmonella, Giardia), FTT CD8: 655 12 1.5/M Middle Pneumonia (unspecified) No CD3: 2130 CD19: 540 PHA: nl East/ Thrush CD4: 1250 CD56: 60 Arabic CD8: 740 13 0.5/M Middle Adenovirus pneumonia No CD3: 1610 CD19: 1060 NT East/ Recurrent pneumonias CD4: 1160 CD56: 330 Arabic (unspecified) CD8: 430 Viral gastroenteritis UTI 14 2/M Middle Recurrent pneumonia No CD3: 501 CD19: 310 PHA: 15% nl East/ (unspecified), bronchiectasis CD4: 290 Arabic CD8: 200 15 2.5/M Caucasian RSV pneumonia; pneumonia No CD3: 231 CD19: 880 PHA: o5% nl (unspecified), rubella-associated CD4: 80 CD56: 544 Con A: o5% nl skin rash and viremia CD8: 123 PWM: o5% nl HSV2 viremia, FTT Candid: 10% nl Tetanus: absent 16 1.9/M Saudi CMV pneumonia x2 Yes CD3: 4995 CD19: 2305 PHA: 59% nl Arabian CMV retinitis CD4: 692 CD56: 307 MLC: nl FTT CD8: 3842 Norovirus gastroenteritis Auto-immune hepatitis Abbreviations: CMV ¼ cytomegalovirus; ECHO ¼ enteric cytopathic human orphan; F ¼ female; FTT ¼ failure to thrive; HCT ¼ haematopoietic cell transplantation; HX ¼ history of; M ¼ male; nl ¼ lower limit of normal control range or % of normal control of the day; NK ¼ natural killer; NT ¼ not tested; PCP ¼ Pneumocystis carinii; PWN ¼ pokeweed mitogen; RSV ¼ respiratory syncytial virus; UTI ¼ urinary tract infection; VZV ¼ varicella zoster virus. aPatients in bold rejected their primary graft. thiotepa and CY (n ¼ 1), CY and fludarabine (n ¼ 1), or CY alone (n ¼ 1). (n ¼ 2), fludarabine, CY, anti-CD45 and anti-CD52 (n ¼ 1), or low-dose CY, Recipients of T-cell-depleted SCT received anti-thymocyte globulin (n ¼ 6) fludarabin 200 cGy of single-dose TBI and post-transplant CY. Post- or anti-CD52 (Campath 1H, n ¼ 1) to prevent graft failure. Recipients of an transplant prophylaxis against GVHD included combinations of cyclosporin unmodified BM or PBSCT were cytoreduced with BU, fludarabine, CY or tacrolimus and mycophenolic acid. The two cord blood recipients (n ¼ 2), thiotepa and CY (n ¼ 1), melphalan, fludarabine and anti-CD52 received treosulfan and fludarabine without serotherapy.13 & 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013) 226 – 232 228 Bone Marrow Transplantation (2013) 226 – 232 Table 2.
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