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Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome

2016; Elsevier BV; Volume: 139; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2016.09.040

1097-6825

Zohreh Nademi, Mary Slatter, Christopher C. Dvorak, Bénédicte Neven, Alain Fischer, Felipe Suárez, Claire Booth, Kanchan Rao, Alexandra Laberko, J. Rodina, Yves Bertrand, Sylwia Kołtan, Robert Dębski, Terence Flood, Mario Abinun, Andrew R. Gennery, Sophie Hambleton, Stephan Ehl, Andrew J. Cant,

Blood disorders and treatments

The phenotype of activated PI3K-δ syndrome (APDS) includes recurrent respiratory infections, severe viral infections, autoimmunity, lymphoproliferation/lymphoma and neurodevelopmental problems, accompanied by variable lymphopenia with increased circulating transitional B lymphocytes, increased IgM and impaired vaccine responses, and reduced naive and increased senescent T lymphocytes with reduced proliferative capacity.1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (427) Google Scholar, 2Walsh C.M. Fruman D.A. Too much of a good thing: immunodeficiency due to hyperactive PI3K signalling.J Clin Invest. 2014; 124: 3688-3690Crossref PubMed Scopus (13) Google Scholar, 3Kang S. Denley A. Vanhaesebroeck B. Vogt P.K. Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase.Proc Natl Acad Sci. 2006; 103: 1289-1294Crossref PubMed Scopus (248) Google Scholar Although variable in severity, it can present as or evolve into a profound combined immunodeficiency, justifying the consideration of hematopoetic stem cell transplantation (HSCT). We report the first series of HSCT in this disorder. APDS is associated with dominantly inherited gain-of-function mutations in PIK3CD.1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (427) Google Scholar A similar clinical phenotype is associated with a heterozygous splice site mutation in PIK3R1.4Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Scopus (185) Google Scholar Angulo et al1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (427) Google Scholar reported 17 patients with the E1021K mutation, and Lucas et al4Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Scopus (185) Google Scholar, 5Lucas C.L. Kuehn H.S. Zhao F. Niemela J.E. Deenick E.K. Palendira U. et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (452) Google Scholar 14 patients who bore heterozygous gain-of-function mutations in PIK3CD.5Lucas C.L. Kuehn H.S. Zhao F. Niemela J.E. Deenick E.K. Palendira U. et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (452) Google Scholar, 6Vermijlen D. Braun M.Y. Marchant A. Do PI3-kinase mutations drive T cells insane?.Cell Mol Immunol. 2014; 11: 320-322Crossref PubMed Scopus (2) Google Scholar Subsequently, a similar clinical phenotype was associated with a heterozygous splice site mutation in PIK3R1, reported by Deau et al7Deau M.C. Heurtier L. Frange P. Suarez F. Bole-Feysot C. Nitschke P. et al.A human immunodeficiency caused by mutations in the PIK3R1 gene.J Clin Invest. 2014; 124: 3923-3928Crossref PubMed Scopus (173) Google Scholar in 4 patients. Lucas et al4Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Scopus (185) Google Scholar later described hyperactive PI3K signaling in 4 patients who experienced recurrent sinopulmonary infections and lymphoproliferation. Lougaris et al8Lougaris V. Faletra F. Lanzi G. Vozzi D. Marcuzzi A. Valencic E. et al.Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype.Clin Immunol. 2015; 159: 33-36Crossref PubMed Scopus (43) Google Scholar also reported heterozygous splice site mutations in PIK3R1 in 4 patients, and Petrovski et al9Petrovski S. Parrott R.E. Roberts J.L. Huang H. Yang J. Gorentla B. et al.Dominant splice site mutations in PIK3R1 cause hyper IgM syndrome, lymphadenopathy and short stature.J Clin Immunol. 2016; 36: 462-471Crossref PubMed Scopus (43) Google Scholar later described 4 patients with hyper-IgM syndrome and short stature who had dominant splice site mutations in PIK3R1. Patients with APDS may benefit from rapamycin or other inhibitors of PI3K.1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (427) Google Scholar, 2Walsh C.M. Fruman D.A. Too much of a good thing: immunodeficiency due to hyperactive PI3K signalling.J Clin Invest. 2014; 124: 3688-3690Crossref PubMed Scopus (13) Google Scholar, 5Lucas C.L. Kuehn H.S. Zhao F. Niemela J.E. Deenick E.K. Palendira U. et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (452) Google Scholar Despite reports of impressive responses, not all patients achieve durable disease remission. Chronic morbidity and death from severe infection and lymphoma are reported such that HSCT is a relevant consideration. We report 11 patients who have undergone HSCT in 7 pediatric centers. The diagnosis was made before HSCT (n = 5) or retrospectively in 6 patients who had undergone HSCT for life-threatening immune deficiency. All patients had the E1021K PIK3CD mutation except 1 who bore the typical PIK3R1 mutation. Pretransplant clinical features are summarized (Table I). Four of 11 had a family history of hypogammaglobulinemia, malignancy, or recurrent infections in a first-degree relative. All experienced recurrent sinopulmonary infections and 4 developed bronchiectasis. Four had viral skin infections such as Molluscum, herpetic skin lesions, or warts. Generalized lymphadenopathy and hepatosplenomegaly were present in 8 of 11. Systemic viral infections including viremia with Herpes family viruses were seen in 6 of 11 patients. Four patients had gastrointestinal symptoms, for example, enteropathy (n = 2), colitis (n = 2), or lymphoid proliferation and intestinal obstruction (n = 1) requiring hemicolectomy. Two patients with Cryptosporidium infection developed hepatic fibrosis; sclerosing cholangitis was seen in a third. Two developed renal impairment; 1 had glomerulonephritis with positive anti-DNA antibodies and in another, renal histology showed sclerosis.Table IPatients' characteristicsSitePatient no.Age at HSCT (y)SexMedical historyFHMutationDonor sourceConditioningCell doses (× 106/kg)GvHD prophylaxisUK (NCL)Patient 116MSinopulmonary infectionsLymphadenopathy MolluscumYE1021KMUD, PB10/10Treo42/Flu150Campath 1H8.5CSA/MMFUK (NCL)Patient 28MLymphadenopathyEnteropathy MastocytomaViral infections (CMV, EBV)CryptosporidiumHepatic fibrosisNE1021KMMUD, PB7/10Treo42/Flu150Campath 1H21.2CSA/MMFUK (NCL)Patient 36MSinopulmonary infectionsBronchiectasisSevere wart/herpetic lesionYc.1299+1G>Aspliced mutationexon 11 skippingMUD, PB10/10Treo42/Flu150Campath 1H11.7CSA/MMFUK (London)Patient 47MSinopulmonary infectionsYE1021KMUD, PB10/10Mel140/Flu150Campath 1H20.99CSA/MMFUSAPatient 59MSinopulmonary infectionsBronchiectasisIntestinal lymphoid hyperplasiaIntestinal obstructionHemicolectomyHepatosplenomegalyMolluscumViral infections (VZV)NE1021KMUD, PB10/10Mel100/Flu200/TT10Campath 1H5Tac/MTXPolandPatient 67MSinopulmonary infectionsLymphadenopathyHepatosplenomegalyColitisViral infections (CMV, ADV)NE1021KMSD, BM10/10Bu/FluThymoglobin390CSA/MMFRussiaPatient 75MSinopulmonary infectionsPancytopenia, colitisSepsis, MOF, RFNE1021KMUD, PB10/10Treo42/Flu150/RTX100/Timo 514.5MMF/AbataceptFrance (Lyon)Patient 810MSinopulmonary infectionsBronchiectasisLymphadenopathyHepatosplenomegalyCryptosporidiumHepatic fibrosisViral infections (CMV, EBV, ADV)NE1021KMMUD, CB4/6Mel140/Flu150ATG0.54CSA/SteroidFrance (Paris)Patient 913FSinopulmonary infectionsLymphadenopathyTonsilectomyGlomerulonephritisYE1021KMSD, BM10/10Bu/Cyclo4.6CSA/MTXFrance (Paris)Patient 108FSinopulmonary infectionsBronchiectasisLymphadenopathyHepatomegalySclerosing cholangitisFTTNE1021KMSD, BM10/10Mel120/Flu 150ATG6.8CSAFrance (Paris)Patient 1118MSinopulmonary infections LymphadenopathySplenomegalyMolluscumViral infections (VZV)AIHAAspergillosisNE1021KMSD, PB10/10Bu/cyclo160 mg/kg2.74CSA/MMFADV, Adenovirus; ATG, antithymocyte globulin; BM, bone marrow; CB, cord blood; CMV, cytomegalovirus; CSA, cyclosporin; cyclo, cyclophosphamide; F, female; FH, family history; Flu, fludarabine; FTT, failure to thrive; M, male; Mel, melphalan; MMF, mycophenolate mofetil; MMUD, mismatched unrelated donor; MOF, multiorgan failure; MTX, methoteroxate; MUD, matched unrelated donor; NCL, Newcastle; PB, peripheral blood; RF, renal failure; RTX, rituximab; Tac, tacrolimus; Treo, treosulfan; TT, thiotepa; VZV, varicella-zoster virus. Open table in a new tab ADV, Adenovirus; ATG, antithymocyte globulin; BM, bone marrow; CB, cord blood; CMV, cytomegalovirus; CSA, cyclosporin; cyclo, cyclophosphamide; F, female; FH, family history; Flu, fludarabine; FTT, failure to thrive; M, male; Mel, melphalan; MMF, mycophenolate mofetil; MMUD, mismatched unrelated donor; MOF, multiorgan failure; MTX, methoteroxate; MUD, matched unrelated donor; NCL, Newcastle; PB, peripheral blood; RF, renal failure; RTX, rituximab; Tac, tacrolimus; Treo, treosulfan; TT, thiotepa; VZV, varicella-zoster virus. Five received immunosuppression (steroid ± sirolimus) and 7 received immunoglobulin replacement pretransplant. However, the applied treatment proved ineffective in preventing recurrent infections, generalized or intestinal lymphoproliferations, and in 1 case malignant lymphoma before transplant, leading to the decision to perform HSCT (Table I). Age at transplant ranged from 5 to 23 years. The source of stem cells was peripheral blood in 7 of 11, cord blood in 1, and bone marrow in 3. Five received matched (10/10) unrelated donor stem cells, 4 had a matched sibling donor, and 2 had mismatched unrelated donors (7 of 10 peripheral blood or 4 of 6 cord blood, respectively). All except 2 received fludarabine, in combination with treosulfan (n = 4), melphalan (n = 4), and busulfan in 1 patient. Two received busulfan with cyclophosphamide. One received thiotepa in addition to fludarabine and melphalan because his activated immune system was considered to pose a risk of rejection. All except 2 received serotherapy. Five received alemtuzumab, whereas others received antithymocyte globulin (n = 3) or rituximab (n = 1). CD34+ cell doses ranged from 0.54 × 106/kg to 390 × 106/kg. Posttransplant characteristics are detailed in Table II. Neutrophil engraftment (≥0.5 × 109/L) was at 13 to 31 days and platelet engraftment (≥20 × 109/L) 9 to 31 days posttransplant. Nine sustained chimerism (>90%) long-term, whereas 2 had slipping chimerism (Table II). T-lymphocyte chimerism in patient 3 declined to 38% with 18% donor myeloid cells; he has low IgG2, poor response to conjugate pneumococcal vaccine, new wart lesions, and chest infections, suggesting possible recurrence of APDS. Patient 10 had low chimerism of 26% on whole blood requiring second transplant, which was refused by her parents. Nine (81%) developed acute graft versus host disease (GvHD), mostly skin grade I to II, whereas 2 showed either gut or liver GvHD grade I. All patients responded to systemic steroid and/or topical treatment. Seven patients showed viral reactivation posttransplant, which responded to antiviral treatment. Patient 2 developed EBV lymphoproliferative disease posttransplant and responded to cyclosporine discontinuation. Patient 3 developed autoimmune hemolytic anemia (AIHA) postshingles. It resolved. Patient 9 developed varicella-zoster virus encephalitis 5 months posttransplant with full recovery.Table IIPost-HSCT characteristicsSitePatient no.Neut outcome engraftPLT engraftChimerism %GvHD site/gradeIVIGAb respCD3 (NR) (cells/μL)Naive TProliferation assayComplication post- HSCTF/UUK (NCL)Pt 1D+21D+9100 WBSkin GIIOnND143 (690-2540)NANARenal impairmentAIHAA/W1 yUK (NCL)Pt 2D+15D+9100 WBSkin GIOffHib: lowPresent to 11/13 prevenar2400 (800-3500)PNLEBV LPD AI cytopeniaA/W4 yUK (NCL)Pt 3D+31D+12CD15 18CD3 38Skin GIIOffPresent to 3/13 of prevenarNormal Tet/Hib534 (700-4200)NANAAIHA Clostridium difficle carrierAlive3 yUK (London)Pt 4D+14D+10CD15 95CD3 98NOffTet: NL MMR: P1480 (700-4200)NANDLRTI ShinglesA/W2 yUSAPt 5D+15D+24CD15 100CD3 88B 100NOffND56 (690-2540)NANLNoneA/W10 moPolandPt 6D+21D+2999 WBGut GIOnND790 (700-4200)PNDChronic sinusitis requiring surgeryA/W8 yRussiaPt 7D+13D+1399 WBSkin GIIN/AN/AN/AN/AN/ARFEnterocolitisRIP (D+75)CMV/ADVpneumoniaResp failureFrance (Lyon)Pt 8D+24D+31100 WBSkin GIOffNLNLPNLVZVA/W10 yFrance (Paris)Pt 9D+21D+25100 WBSkin GIIOffNA1252 (690-2540)NANAEncephalitisA/W16 yFrance (Paris)Pt 10D+17NA26 WBLiver GIOnNA1349 (690-2540)PNDChest infectionsAlive16 yFrance (Paris)Pt 11D+12D+10100 WBSkin GIN/AN/AN/AN/AN/ARFRIPIdiopathicpneumoniasyndromeADV, Adenovirus; AI, autoimmune; A/W, alive and well; CMV, cytomegalovirus; Engraft, engraftment; Hib, hemophilus influenza B vaccine; LPD, lymphoproliferative disease; LRTI, lower respiratory tract infection; MMR, mumps/measles/rubella; NCL, Newcastle; Neut, neutrophil; N/A, not applicable; NA, not available; ND, not done; NL, normal; P, present; Pt, patient; PLT, platelet; Resp, respiratory; RF, renal failure; RIP, rest in peace; Tet, tetanus; VZV, varicella-zoster virus; WB, whole blood. Open table in a new tab ADV, Adenovirus; AI, autoimmune; A/W, alive and well; CMV, cytomegalovirus; Engraft, engraftment; Hib, hemophilus influenza B vaccine; LPD, lymphoproliferative disease; LRTI, lower respiratory tract infection; MMR, mumps/measles/rubella; NCL, Newcastle; Neut, neutrophil; N/A, not applicable; NA, not available; ND, not done; NL, normal; P, present; Pt, patient; PLT, platelet; Resp, respiratory; RF, renal failure; RIP, rest in peace; Tet, tetanus; VZV, varicella-zoster virus; WB, whole blood. All surviving patients have ceased immunosuppression and immunoglobulin replacement therapy except 3; patient 1 developed AIHA, patient 6 will cease immunoglobulin replacement therapy in the near future, and patient 10 had low donor chimerism. Two patients had low absolute CD3 numbers post-HSCT; patient 1 developed AIHA and was on immunosuppression, and patient 5 had lymphoproliferations before HSCT. Nine patients (81%) are alive with post-HSCT follow-up of 8 months to 16 years. Patient 7 died 75 days post-HSCT because of progressive renal failure, respiratory failure postcytomegalovirus, and adenovirus chest infection and pulmonary hemorrhage. Patient 11 died 70 days posttransplant because of idiopathic pulmonary syndrome. This case series shows that HSCT can achieve a complete cure with no need for ongoing treatment. The survival of 81% is similar to that seen after HSCT for other combined primary immunodeficiencies.10Dvorack C.C. Cowan M.J. Hematopoietic stem cell transplantation for primary immunodeficiency disease.Bone Marrow Transplant. 2008; 41: 119-126Crossref PubMed Scopus (64) Google Scholar The question on nonhematopoietic aspects of the disease phenotype remains incompletely answered. Furthermore, it remains to be addressed, what level of donor chimerism is needed to prevent immunopathological manifestations of disease including lymphoproliferation and lymphoma. The conditioning regimens can affect GvHD and immune recovery. The precise indications and optimal time point for HSCT need to be defined. In particular, the risks of transplant must be judged against the benefit of treatment with rapamycin or inhibitors of PI3K, which are currently being studied in clinical trials.1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (427) Google Scholar, 2Walsh C.M. Fruman D.A. Too much of a good thing: immunodeficiency due to hyperactive PI3K signalling.J Clin Invest. 2014; 124: 3688-3690Crossref PubMed Scopus (13) Google Scholar, 5Lucas C.L. Kuehn H.S. Zhao F. Niemela J.E. Deenick E.K. Palendira U. et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (452) Google Scholar A prospective patient registry (http://esid.org/Working-Parties/Registry/Studies/APDS-Registry) may help to better identify patients who will benefit from early HSCT. We thank Ms Virginie Courteille (SCETIDE Registry) and Patricia Tierney for data input.