Pediatr Blood Cancer BRIEF REPORT Successful Hematopoietic Cell Transplantation in a Patient With X-linked Agammaglobulinemia and Acute Myeloid Leukemia Rolla F. Abu-Arja, MD, 1 * Leah R. Chernin, DO, 2 Ghada Abusin, MD, MS, 3 Jeffery Auletta, MD, 1 Linda Cabral, PA, 4 Rachel Egler, MD, 4 Hans D. Ochs, MD, 5 Troy R. Torgerson, MD, Jesus Lopez-Guisa, PhD, 5 Robert W. Hostoffer, DO, 2 Haig Tcheurekdjian, MD, 2 and Kenneth R. Cooke, MD 6 INTRODUCTION X-linked agammaglobulinemia (XLA) is characterized by early-onset bacterial infections, marked reduction in all classes of serum immunoglobulins, and the near absence of mature CD19 þ B-cells.[1] XLA is caused by mutations in the Bruton’s tyrosine kinase (BTK) gene, which is essential for B-cell development.[2–4] Although an increased risk of malignancy has been previously described in patients with XLA,[5,6] acute myeloid leukemia (AML) and the use of unrelated hematopoietic cell transplantation (HCT) has not been reported. We present the first reported case of AML in a pediatric patient with XLA. Although HCT was initiated to treat the patient’s relapsed AML, it also completely corrected his XLA phenotype. CASE PRESENTATION The male patient initially presented at age 5 years with a history of recurrent sino-pulmonary infections, intermittent fevers, spleno- megaly, and pancytopenia. Bone marrow aspiration/biopsy (BMA/ Bx) revealed B-cell hypoplasia with no evidence of malignancy. BM immunophenotyping demonstrated complete absence of CD19 þ B-cells. Immunoglobulin levels were very low. Genomic DNA analysis revealed a novel point mutation in BTK, 192 nucleotides upstream of the initiation (ATG) codon (c.1-192A>G), affecting the promoter region of BTK and confirming the diagnosis of XLA. The patient was started on monthly intravenous immunoglobulin (IVIG) infusions. His splenomegaly resolved, and he had no further infections after the initiation of IVIG therapy. At age 13 years, a routine laboratory evaluation revealed pancytopenia. BMA/Bx showed 20% blast partially myeloperox- idase positive and containing Auer rods with an immunophenotype profile (CD13 þ , CD15 dim, CD19  , CD33 þ , CD 34 þ , and CD117 þ ) consistent with the diagnosis of AML. No cytogenetic abnormalities were detected and FLT3 mutation was negative. Because AML has not been previously reported in XLA, flow analysis of peripheral blood mononuclear cells was performed to assess BTK expression and to confirm that the patient’s B-cells lacked BTK. Consistent with the BTK mutation identified at original presentation, the patient was found to have markedly reduced numbers of lymphocytes expressing BTK (Fig. 1A) and reduced expression in his monocytes as well (Fig. 1B). Because haploinsufficiency of the hematopoietic transcription factor GATA2 has been associated with monocytope- nia, B-cell deficiency, and AML,[7] we sequenced the GATA2 gene, which was wild type. Resequencing of genomic DNA confirmed the c.1-192A>G mutation (AAAGGGAACTG to AAAGGGAGCTG) affecting the invariable core sequence (GGAA) located within the critical Pu.1 transcription factor binding site of the BTK-promoter region, which is required for normal BTK expression.[8] Reduced BTK expression in the patient’s mononuclear cells seen by flow cytometry is compatible with a mutation in the Pu.1 transcription factor binding site.[9] Furthermore, the small amount of BTK still produced is expected to be functionally normal as the coding region is unaffected, thus allowing for the production of a minute number of B- cells (Fig. 1A). There has been one previously reported XLA patient with decreased BTK expression due to a BTK mutation in the promoter region within the Pu.1 site.[10] This patient’s mutation was reported to be an A to G mutation located at 193 base pairs upstream of the initiation codon (c.1-193A>G). Treatment for his newly diagnosed AML included chemothera- py per the standard arm of Children’s Oncology Group study AAML0531. His AML was in complete remission at the end of induction II. Unfortunately, the patient suffered an isolated X-linked agammaglobulinemia (XLA) is a primary immunodefi- ciency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19 þ B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient’s leukemia. Pediatr Blood Cancer # 2015 Wiley Periodicals, Inc. Key words: acute myeloid leukemia; stem cell transplantation; X-linked agammaglobulinemia 1 Pediatric Blood and Marrow Transplant Program, Nationwide Child- ren’s Hospital, Columbus, Ohio; 2 Allergy/Immunology Associates, Inc., Case Western Reserve University, Cleveland, Ohio; 3 Pediatric Bone Marrow Transplant Program, University of Iowa Children’s Hospital, Iowa City, Iowa; 4 Pediatric Bone Marrow Transplant, Rainbow Babies and Children’s Hospital, Case Medical Center, Cleveland, Ohio; 5 University of Washington and Seattle Children’s Research Institute, Seattle, Washington; 6 Pediatric Blood and Marrow Transplant, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland Dr. Haig Tcheurekdjian and Dr. Kenneth R.Cooke contributed equally as senior authors.  Correspondence to: Rolla Abu-Arja, Pediatric Hematology/Oncology/ Bone Marrow Transplant, Nationwide Children’s Hospital, 700 Children’s Drive, ED557, Columbus, OH 43205. E-mail: rolla.abu-arja@nationwidechildrens.org Received 20 February 2015; Accepted 12 March 2015  C 2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25554 Published online in Wiley Online Library (wileyonlinelibrary.com).