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Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome

2014; Elsevier BV; Volume: 134; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2014.02.020

1097-6825

Sven Kracker, James Curtis, Mohammad A. A. Ibrahim, Anna Šedivá, J R Salisbury, Vít Campr, Marianne Debré, David Edgar, Kohsuke Imai, Capucine Pïcard, Jean‐Laurent Casanova, Alain Fischer, Sergey Nejentsev, Anne Durandy,

Blood disorders and treatments

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a novel autosomal-dominant primary immunodeficiency (PID) caused by a heterozygous gain-of-function mutation in the PIK3CD gene encoding the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (418) Google Scholar The c.3061G>A mutation results in a substitution of a glutamic acid by a lysine at position 1021 (E1021K). This new PID is characterized by recurrent respiratory infections, leading to bronchiectasis, progressive lymphopenia, and defective antibody production. Both T- and B-cell compartments are affected as shown by the propensity of CD4+ and CD8+ T cells to die after in vitro stimulation and their poor capacity for cytokine production, as well as an immunoglobulin class switch recombination defect (CSR-D). Most of the cases have an increase in serum IgM levels and a decrease in IgG2 isotype, while total IgG and IgA levels can be either normal or strongly decreased. The clinical presentation is variable, ranging from combined immunodeficiency requiring hematopoietic stem cell transplantation to an isolated primary antibody deficiency that can be well controlled by IgG substitution. To identify new patients with APDS, we genotyped the PIK3CD gene at position c.3061G as described previously1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (418) Google Scholar in a cohort of 139 patients with immunologic phenotype of immunoglobulin CSR-D. We found 8 new patients with APDS with the E1021K heterozygous mutation in the PIK3CD gene (see Table E1, Table E2 in this article's Online Repository at www.jacionline.org) in addition to the 17 described previously,1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (418) Google Scholar bringing the total number of known patients carrying this PIK3CD mutation to 25. We noticed that among these 8 new patients with APDS, 2 developed B-cell lymphomas, suggesting that a constitutively active PI3Kδ predisposes to malignancies. These 2 cases are herein reported (Table I, Table II).Table ISummary of clinical and immunologic features of APDS patients with lymphoma occurrenceFeaturePatientP1P2Year of birth19861990Age of onset2 y5 moMain clinical featuresRecurrent LRT infections, liver damage, HMG, SMG, lymphadenopathyRecurrent LRT infections bronchiectasis, chronic diarrhea, failure to thrive HMG, SMGCytopeniaNeutropeniaMain biological featuresLymphopeniaLymphopenia Age2 y5 y IgM (g/L) (N)4.25 (0.58-1.53)4.5 (0.54-1.55) IgG (g/L) (N)5.7 (3.35-8.96) 3)IgG2 (N)1.5 (>0.30)IgG3 (N)0.64 (>0.12)IgG4 (N)0.3 (>0.04)MalignanciesHigh-grade DLBCL of the biliary tract (EBV−, Bcl-6+; age 8 y);high-grade DLBCL of the colon (EBV−, Bcl-6−; stage IVB; age 19 y)Hodgkin lymphoma stage IIITreatmentIVIgG from 3 y on chemotherapy, rituximabIVIgG from 7 y on chemotherapy, radiotherapy (11 y)OutcomeDied from large-bowel perforation and bleeding postchemotherapyIn remission, aliveHMG, Hepatomegaly; IVIgG, intravenous IgG; LRT, low respiratory tract infections; N, normal values for age; SCIgG, subcutaneous IgG; SMG, splenomegaly, WHO classification; WHO, World Health Organization. Open table in a new tab Table IILymphocyte subsets of APDS patients with lymphoma occurrenceLymphocyte populationPatientP1P2Age at analysis (y)1811Number of lymphocytes (μL)790∗Value < normal (see Shearer et alE2).1190∗Value < normal (see Shearer et alE2).CD19+ (μL)104∗Value < normal (see Shearer et alE2).3∗Value < normal (see Shearer et alE2).CD3+CD4+ (μL)245∗Value < normal (see Shearer et alE2).369∗Value < normal (see Shearer et alE2).CD3+CD8+ (μL)349584CD16+CD56+ (μL)55∗Value < normal (see Shearer et alE2).119∗ Value < normal (see Shearer et alE2Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar). Open table in a new tab Patient 1 has no familial history of PID, but his mother died at age 35 years of subarachnoid hemorrhage. He was referred to our hospital at the age of 2 years with recurrent bronchopulmonary infections, lymphadenopathy, hepatosplenomegaly, and liver disease (elevated transaminases and portal septal fibrosis at liver biopsy). He had increased serum IgM levels (4.25 g/L), normal IgG levels (5.7 g/L), and decreased IgA levels (0.65 g/L), compatible with the diagnosis of CSR-D. The CD40L and CD40 defects were excluded and intravenous IgG substitution was initiated. At age 8 years, he developed a high-grade diffuse large B-cell lymphoma (DLBCL, World Health Organization classification) of the biliary tract (Fig 1, A-C). In situ hybridization for EBV was negative, and Bcl-6 was expressed as shown by immunohistochemistry. The patient recovered after 9 courses of chemotherapy (UKCCSG 9002 protocolE1Atra A. Imeson J.D. Hobson R. Gerrard M. Hann I.M. Eden O.B. et al.Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol.Br J Cancer. 2000; 82: 1396-1402Crossref PubMed Scopus (55) Google Scholar). At age 19 years, under IgG substitution, he again developed a high-grade EBV(−) DLBCL of the colon, which was found to be Bcl-6 negative (Fig 1, D-F). He received cyclophophamide, vincristine, steroids plus rituximab. He died from large-bowel perforation and bleeding 12 days after the third course of chemotherapy.Patient 2 belongs to a family in which 2 siblings were reported as suffering from a CSR-D (data from the affected sister P7; see Table E1, Table E2). From the age of 5 months, he suffered recurrent upper (recurrent acute otitis media) and lower respiratory tract infections complicated by bronchiectasis, chronic noninfectious diarrhea with malabsorption syndrome, and failure to thrive. Other infections were also noticed, including pericarditis caused by Echo virus infection and recurrent synovitis. The diagnosis of CSR-D was made according to his familial history and IgG substitution was started. At age 6 and 8 years, he displayed episodes of massive enlargement of lymph nodes (cervical and mesenteric) with no malignant feature at biopsy. Serum immunoglobulin levels revealed an increase in IgM (4.5 g/L at 5 years and 13 g/L at 11 years) levels and a decrease in IgG ( A mutation results in a substitution of a glutamic acid by a lysine at position 1021 (E1021K). This new PID is characterized by recurrent respiratory infections, leading to bronchiectasis, progressive lymphopenia, and defective antibody production. Both T- and B-cell compartments are affected as shown by the propensity of CD4+ and CD8+ T cells to die after in vitro stimulation and their poor capacity for cytokine production, as well as an immunoglobulin class switch recombination defect (CSR-D). Most of the cases have an increase in serum IgM levels and a decrease in IgG2 isotype, while total IgG and IgA levels can be either normal or strongly decreased. The clinical presentation is variable, ranging from combined immunodeficiency requiring hematopoietic stem cell transplantation to an isolated primary antibody deficiency that can be well controlled by IgG substitution. To identify new patients with APDS, we genotyped the PIK3CD gene at position c.3061G as described previously1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (418) Google Scholar in a cohort of 139 patients with immunologic phenotype of immunoglobulin CSR-D. We found 8 new patients with APDS with the E1021K heterozygous mutation in the PIK3CD gene (see Table E1, Table E2 in this article's Online Repository at www.jacionline.org) in addition to the 17 described previously,1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (418) Google Scholar bringing the total number of known patients carrying this PIK3CD mutation to 25. We noticed that among these 8 new patients with APDS, 2 developed B-cell lymphomas, suggesting that a constitutively active PI3Kδ predisposes to malignancies. These 2 cases are herein reported (Table I, Table II). HMG, Hepatomegaly; IVIgG, intravenous IgG; LRT, low respiratory tract infections; N, normal values for age; SCIgG, subcutaneous IgG; SMG, splenomegaly, WHO classification; WHO, World Health Organization. Patient 1 has no familial history of PID, but his mother died at age 35 years of subarachnoid hemorrhage. He was referred to our hospital at the age of 2 years with recurrent bronchopulmonary infections, lymphadenopathy, hepatosplenomegaly, and liver disease (elevated transaminases and portal septal fibrosis at liver biopsy). He had increased serum IgM levels (4.25 g/L), normal IgG levels (5.7 g/L), and decreased IgA levels (0.65 g/L), compatible with the diagnosis of CSR-D. The CD40L and CD40 defects were excluded and intravenous IgG substitution was initiated. At age 8 years, he developed a high-grade diffuse large B-cell lymphoma (DLBCL, World Health Organization classification) of the biliary tract (Fig 1, A-C). In situ hybridization for EBV was negative, and Bcl-6 was expressed as shown by immunohistochemistry. The patient recovered after 9 courses of chemotherapy (UKCCSG 9002 protocolE1Atra A. Imeson J.D. Hobson R. Gerrard M. Hann I.M. Eden O.B. et al.Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol.Br J Cancer. 2000; 82: 1396-1402Crossref PubMed Scopus (55) Google Scholar). At age 19 years, under IgG substitution, he again developed a high-grade EBV(−) DLBCL of the colon, which was found to be Bcl-6 negative (Fig 1, D-F). He received cyclophophamide, vincristine, steroids plus rituximab. He died from large-bowel perforation and bleeding 12 days after the third course of chemotherapy. Patient 2 belongs to a family in which 2 siblings were reported as suffering from a CSR-D (data from the affected sister P7; see Table E1, Table E2). From the age of 5 months, he suffered recurrent upper (recurrent acute otitis media) and lower respiratory tract infections complicated by bronchiectasis, chronic noninfectious diarrhea with malabsorption syndrome, and failure to thrive. Other infections were also noticed, including pericarditis caused by Echo virus infection and recurrent synovitis. The diagnosis of CSR-D was made according to his familial history and IgG substitution was started. At age 6 and 8 years, he displayed episodes of massive enlargement of lymph nodes (cervical and mesenteric) with no malignant feature at biopsy. Serum immunoglobulin levels revealed an increase in IgM (4.5 g/L at 5 years and 13 g/L at 11 years) levels and a decrease in IgG (<1.9 g/L) and IgA (0.41 g/L) levels. At age 11 years, he had a new episode of cervical lymph nodes enlargement that led to the diagnosis of Hodgkin disease, histologic type nodular sclerosis, stage III, with localization to cervical, mediastinum, retroperitoneum, and spleen (the EBV status was unknown and could not be studied retrospectively) (Fig 1, G-I). The patient received chemotherapy and radiotherapy with irradiation of regions above and below the diaphragm, which induced complete remission. He is now well on IgG substitution and prophylactic antibiotherapy with a follow-up of more than 10 years. These observations extend our previous data reporting 1 case of marginal zone B-cell lymphoma in an adult patient with APDS.1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (418) Google Scholar Moreover, a recent study further reports 1 patient with APDS who developed an EBV+ diffuse B-cell lymphoma. Interestingly, authors describe a similar PID phenotype with 2 other gain-of-function mutations (E525K and N334K) in the PIK3CD gene, including 1 case of EBV+ nodular sclerosis form of classical Hodgkin lymphoma (E525K).2Lucas 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 p110delta result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (437) Google Scholar Altogether these observations pinpoint to the fact that PI3Kδ hyperactivation predisposes to multiple types of B-cell lymphomas. Activation of the PI3K pathway is associated with malignant transformations, and it has been shown that overexpression of p110δ can transform cells.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 U S A. 2006; 103: 1289-1294Crossref PubMed Scopus (246) Google Scholar Constitutive PI3K activation has been found in B-cell malignancies, for example, Burkitt lymphomas.4Sander S. Calado D.P. Srinivasan L. Kochert K. Zhang B. Rosolowski M. et al.Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis.Cancer Cell. 2012; 22: 167-179Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 5Rickert R.C. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies.Nat Rev Immunol. 2013; 13: 578-591Crossref PubMed Scopus (211) Google Scholar Recently, somatic E1021K mutations of p110δ have been detected in DLBCLs from 2 patients6Zhang J. Grubor V. Love C.L. Banerjee A. Richards K.L. Mieczkowski P.A. et al.Genetic heterogeneity of diffuse large B-cell lymphoma.Proc Natl Acad Sci U S A. 2013; 110: 1398-1403Crossref PubMed Scopus (406) Google Scholar similar to our first patient, which further supports our observation that activation of PI3Kδ signaling contributes to B-cell neoplasia. We propose that a combination of defective T-cell–mediated immune surveillance and uncontrolled lymphoproliferation of B cells predisposes this PID to B-cell lymphomagenesis. So far, only a minority of patients carrying the PIK3CD mutation (5 out of 39, 13%) had been diagnosed with lymphomas. However, the risk of malignancies is likely to increase with age, modified by additional acquired somatic mutations. Most patients with APDS currently receive treatment with antibiotics and IgG replacement. Such treatment reduces infections but is unlikely to prevent lymphomas. We have found that selective p110δ inhibitors IC87114 and GS-1101 (CAL-101 or Idelalisib) reduce activity of the mutant p110δ in vitro and in cells of patients with APDS ex vivo.1Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (418) Google Scholar GS-1101 has been in clinical trials for the treatment of chronic lymphocytic leukemia, and early data suggest that the drug is well tolerated for extended periods of exposure.7Webb H.K. Chen H. Yu A.S. Peterman S. Holes L. Lannutti B. et al.Clinical pharmacokinetics of CAL-101, a p110{delta} isoform-selective PI3K inhibitor, following single- and multiple-dose administration in healthy volunteers and patients with hematological malignancies.Blood (ASH Ann Meet Abstr). 2010; 116: 1774AGoogle Scholar Therefore, GS-1101 and other selective p110δ inhibitors may provide a novel specific therapy for patients with APDS that prevent lymphoma development. Susceptibility to lymphomas is observed in other well-defined PID, such as the autosomal-dominant hyper-IgE syndrome due to heterozygous mutations in STAT3 and in autosomal-recessive IL10RA or IL10RB deficiencies, suggesting a role for the IL-10R/STAT3 pathway in controlling lymphomagenesis.8Neven B. Mamessier E. Bruneau J. Kaltenbach S. Kotlarz D. Suarez F. et al.A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency.Blood. 2013; 122: 3713-3722Crossref PubMed Scopus (83) Google Scholar Patients with common variable immunodeficiency are also prone to develop lymphomas.9Cunningham-Rundles C. How I treat common variable immune deficiency.Blood. 2010; 116: 7-15Crossref PubMed Scopus (226) Google Scholar Physicians should be aware of this complication that strongly worsens the prognosis for patients with PID. AppendixTable E1Summary of clinical and immunologic featuresFeaturePatientP3P4P5P6P7 (sister of P2)P8Year of birth200619911992199819841999Age of onset (y)2854 y8 y2 yMain clinical featuresRecurrent LRT infections, chronic diarrhea, SMGRecurrent LRT infections, chronic diarrhea, HMG, polyadenopathy, macrocraniaRecurrent LRT infections, chronic diarrhea, SMG, HMG, polyadenopathyRecurrent LRT infections, bronchiectasisRecurrent LRT infectionsRecurrent LRT infections, bacterial pneumonia, chronic diarrhea SMG, HMG, polyadenopathyCytopeniaThrombocytopeniaNeutropenia, AIHA, thrombocytopeniaNeutropeniaNeutropeniaImmunologic featuresLymphopeniaLymphopeniaLymphopeniaLymphopeniaLymphopenia Age2 y 9 mo4 y5 y4 y8 y2 y 8 mo IgM (g/L) (N)3.9 (0.58-1.53)7.23 (0.54-1.55)1.18 (0.54-1.55)2.65 (0.5-2.0)2.28 (0.54-1.55)1.57 (0.58-1.53) IgG (g/L) (N)0.12 (3.35-8.96)4.77 (5.49-11.54)3.98 (5.49-11.54)9.7 (5.49-11.54)8.98 (5.49-11.54)1.30 (3.35-8.96) IgA (g/L) (N)<0.06 (0.27-1.22)0.7 (0.41-1.57)ND (0.41-1.57)0.51 (0.4-2.0)0.30 (0.41-1.57) 3)3.56 (>4)8.88 (>4)IgG2 (N)0.06 (>0.30)1.61 (>0.40)0.1 (>0.40)IgG3 (N)0.02 (>0.12)0.89 (>0.16)0.11 (>0.16)IgG4 (N)0.001 (0-2.10)<0.075 (0-2.10) 0.04)TreatmentIVIgG from 3 yHSCT at 8 y, IVIgG from 8 yIVIgG from 6 y, splenectomy, HSCT at 13 ySCIgG from 4 yIVIgG from 19 yIVIgG from 3 yOutcomeAliveAliveDead (septic shock, mutliorgan failure, 14 y)AliveAliveAliveAIHA, Autoimmune hemolytic anemia; HMG, hepatomegaly; HSCT, hematopoietic stem cell transplantation; IVIgG, intravenous IgG; LRT, low respiratory tract infections; N, normal values for age; SCIgG, subcutaneous IgG; SMG, splenomegaly. Open table in a new tab Table E2Lymphocyte subsetsLymphocyte populationPatientP3P4P5P6P7P8Age at analysis (y)51711112912B-cell phenotype CD19+ (μL)72∗Value < normal.E295∗Value < normal.E225∗Value < normal.E230070∗Value < normal.E24∗Value < normal.E2 CD27+/CD19+ (%)2†Value < normal (laboratory values) (%) for CD27+/CD19+ >10; for IgM−IgD−/CD27+CD19+ (switched memory B cells) >10; normal laboratory values for CD21+CD24++/CD19+ (transitional B cells) 2-8.ND249†Value < normal (laboratory values) (%) for CD27+/CD19+ >10; for IgM−IgD−/CD27+CD19+ (switched memory B cells) >10; normal laboratory values for CD21+CD24++/CD19+ (transitional B cells) 2-8.NDND IgM−IgD−/CD27+CD19+ (%)47NDND9†Value < normal (laboratory values) (%) for CD27+/CD19+ >10; for IgM−IgD−/CD27+CD19+ (switched memory B cells) >10; normal laboratory values for CD21+CD24++/CD19+ (transitional B cells) 2-8.NDND CD21+CD24++/CD19+ (%)3NDNDNDNDNDT-cell phenotype and function Response PHA (proliferation)NormalNormalDiminished (18% of normal)NormalNDNormal CD3+CD4+ (μL)442∗Value < normal.E2456∗Value < normal.E263∗Value < normal.E2660560322∗Value < normal.E2 CD3+CD8+ (μL)585703131∗Value < normal.E2590340259∗Value < normal.E2NK cells CD16+CD56+ (μL)65∗Value < normal.E2380153ND13035∗Value < normal.E2ND, Not determined; NK, natural killer.∗ Value < normal.E2Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar† Value < normal (laboratory values) (%) for CD27+/CD19+ >10; for IgM−IgD−/CD27+CD19+ (switched memory B cells) >10; normal laboratory values for CD21+CD24++/CD19+ (transitional B cells) 2-8. Open table in a new tab AIHA, Autoimmune hemolytic anemia; HMG, hepatomegaly; HSCT, hematopoietic stem cell transplantation; IVIgG, intravenous IgG; LRT, low respiratory tract infections; N, normal values for age; SCIgG, subcutaneous IgG; SMG, splenomegaly. ND, Not determined; NK, natural killer.