key: cord-0010202-76a2wbk2 authors: Geerlinks, Ashley V.; Issekutz, Thomas; Wahlstrom, Justin T.; Sullivan, Kathleen E.; Cowan, Morton J.; Dvorak, Christopher C.; Fernandez, Conrad V. title: Severe, persistent, and fatal T‐cell immunodeficiency following therapy for infantile leukemia date: 2016-06-29 journal: Pediatr Blood Cancer DOI: 10.1002/pbc.26108 sha: 0a247724e3dfa46ce63737d41c355ba675711f67 doc_id: 10202 cord_uid: 76a2wbk2 We describe five cases of children who completed chemotherapy for infantile acute lymphoblastic leukemia (ALL) and soon after were diagnosed with severe T‐cell, non‐HIV immunodeficiency, with varying B‐cell and NK‐cell depletion. There was near absence of CD3(+), CD4(+), and CD8(+) cells. All patients developed multiple, primarily opportunistic infections. Unfortunately, four patients died, although one was successfully treated by hematopoietic stem cell transplantation. These immunodeficiencies appeared to be secondary to intensive infant ALL chemotherapy. Our report highlights the importance of the early consideration of this life‐threatening immune complication in patients who received chemotherapy for infantile ALL. Intensification of therapy for infants with acute lymphoblastic leukemia (ALL) has resulted in fewer relapses, but at the cost of increased morbidity and death, especially during induction therapy. 1, 2 Increased nonhematological toxicity during modern treatment strategies for infant ALL has been reported, but severe immunodeficiency persisting after therapy has not been described. Immunodeficiencies are classified as acquired or primary (PID). Congenital T-cell immunodeficiencies, defined as CD3 + less than 300 cells/ l, 3 are generally more severe, compared to other immunodeficiencies, since T-cells also play a crucial role in the function of Bcells, NK-cells, and macrophages. Chemotherapy is known to induce an immunodeficiency state by significantly depleting T-cells, as well as NK-cells and B-cells. 4, 5 Usually, immune reconstitution begins after completing chemotherapy. In children, greater than 2 years of age, who received intense chemotherapy for treatment of high-risk ALL, T-cell recovery was complete 12-18 months after cessation of chemotherapy. In addition, the absolute CD3 + count at 1 month was greater than 300 cells/ l in these patients. 5, 6 We describe five children who completed treatment for infantile ALL and soon after were diagnosed with persistent severe T-cell, non-HIV, immunodeficiency, with varying B-cell and NK-cell depletion, resulting in severe infections causing death in four and successful hematopoietic stem cell transplantation (HSCT) in one. The immune deficiency appeared to be secondary to their therapy. Our report highlights the importance of considering this complication in patients with infant ALL post chemotherapy. The IWK Health Centre Research Ethics Board reviewed this manuscript and provided a letter of support. We collected data on five infant cases, four females and one male, treated at three centers in North America between 1996 and 2015. Clinical and treatment characteristics are shown in Table 1 We describe the first report of non-HIV, persistent T-cell immunodeficiency, with varying B-cell and NK-cell depletion, in patients with infant ALL following modern intensive chemotherapy. Patients in our cohort remained mildly to severely lymphopenic and flow cytometry demon-strated extremely low CD3 + , CD4 + , and CD8 + T-cell populations consistent with a severe T-cell immunodeficiency despite completion of their chemotherapy treatment 2-13 months prior. We believe it is very unlikely that our patients had unrecognized PID. None of these patients had strong identifiers of PID, such as failure to thrive or intravenous antimicrobial use prior to ALL diagnosis. 10 Patient B did have a distant family history of RAG2 deficiency but she did not carry this mutation. Investigations prior to starting chemotherapy suggested patients A, B, and C had been exposed to viral infections with no major complications. Finally, Patient E had an extensive genetic workup excluding common SCID mutations and Patients A and C had normal TREC assays. Based on the described history and investigations, we concluded these were secondary immunodeficiencies produced by the chemotherapy. Studies of immune reconstitution in children who received chemotherapy for hematologic malignancy demonstrate that in most children total lymphocyte count recovered within 3-6 months. 11 The total B-cell count is normal in most children by 1 month and all children by 6 months after chemotherapy cessation. 6 NK-cells were TA B L E 2 Immunologic investigations assessing immune function and causes of immune deficiency initially thought to totally recover within 1 month of cessation, but more recent studies have shown a delayed drop that may take 6-12 months to fully recover. 6, 12, 13 As for the T-cells, recovery of the CD4 + subset has been shown to have a direct relationship to the intensity of therapy and an inverse relationship with age. 14 This inverse relationship is thought to be because CD4 + T-cells recover more rapidly through a thymicdependent pathway. Normal thymic involution does not begin until approximately 7 years of age. 4 Thymic enlargement post chemotherapy has been demonstrated in pediatric patients. 6 In most children treated for standard-risk and high-risk ALL, CD4 + , and CD8 + T-cells require 3-18 months to recover and the CD3 + count at 1 month was greater than 300 cells/ l regardless of treatment intensity. 5, 6 Despite these prolonged impairments in immune function, severe opportunistic infections are not typically appreciated after cessation of chemotherapy, and death from infection is rare. 13 These T-cell recovery patterns were not seen in our patients. In addition, cyclophosphamide and cytarabine have been associated with depletion of early lineage T-cells, thus affecting T-cell proliferation. 15 Although Patient A was treated prior to cyclophosphamide being eliminated from AALL0631 induction, all of our patients were exposed to cumulative cyclophosphamide doses at least double that of standard-risk or high-risk ALL protocols used in older children. 1 It is possible that these higher doses of cyclophosphamide (and We thank the patients and families described in this series. The authors declare that there is no conflict of interest. HSCT hematopoietic stem cell transplantation PID primary immunodeficiency SCID severe combined immunodeficiency TREC T-cell receptor excision circle Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: a report from the children's oncology group Modifications to induction therapy decrease risk of early death in infants with acute lymphoblastic leukemia treated on Children's Oncology Group P9407 Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience T-cell immunodeficiency following cytotoxic antineoplastic therapy: a review Reduced versus intensive chemotherapy for childhood acute lymphoblastic leukemia: impact on lymphocyte compartment composition Immune reconstitution after childhood acute lymphoblastic leukemia is most severely affected in the high risk group Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study Pediatric Reference Intervals Serum levels of immune globulins in health and disease: a survey Clinical features that identify children with primary immunodeficiency diseases Immune reconstitution in children following chemotherapy for haematological malignancies: a long-term follow-up Recovery of natural killer cells after chemotherapy for childhood acute lymphoblastic leukemia and solid tumors Longitudinal assessment of immunological status and rate of immune recovery following treatment in children with ALL Age, thymopoiesis, and CD4 Tlymphocyte regeneration after intensive chemotherapy Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies Harnessing the biology of IL-7 for therapeutic application Recombinant human interleukin-7 (CYT107) promotes T cell recovery after allogeneic stem cell transplantation Effects of recombinant human interleukin 7 on T cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study IL-7 in human health and disease