Immune reconstitution in children following chemotherapy for acute leukemia.

Although survival rates for pediatric acute lymphoblastic leukemia are now excellent, this is at the expense of prolonged chemotherapy regimens. We report the long-term immune effects in children treated according to the UK Medical Research Council UKALL 2003 protocol. Peripheral blood lymphocyte subsets and immunoglobulin levels were studied in 116 participants, at six time points, during and for 18-month following treatment, with 30-39 patients analyzed at each time point. Total lymphocytes were reduced during maintenance chemotherapy and remained low 18 months following treatment completion. CD4 T cells remained significantly reduced 18 months after treatment, but CD8 cells and natural killer cells recovered to normal values. The fall in naïve B-cell numbers during maintenance was most marked, but numbers recovered rapidly after cessation of treatment. Memory B cells, particularly nonclass-switched memory B cells, remained below normal levels 18 months following treatment. All immunoglobulin subclasses were reduced during treatment compared to normal values, with IgM levels most affected. This study demonstrates that immune reconstitution differs between lymphocyte compartments. Although total B-cell numbers recover rapidly, disruption of memory/naïve balance persists and T-cell compartment persist at 18 months. This highlights the impact of modern chemotherapy regimens on immunity, and thus, infectious susceptibility and response to immunization.

Thirteen-Valent Pneumococcal Conjugate Vaccine in Children With Acute Lymphoblastic Leukemia: Protective Immunity Can Be Achieved on Completion of Treatment.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) are at increased risk of developing invasive pneumococcal disease. This study describes the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) during and after chemotherapy. METHODS: Children with ALL were allocated to study groups and received a single dose of PCV13: group 1, maintenance chemotherapy; group 2, end of chemotherapy; group 3, 6 months after chemotherapy. A protective vaccine response was defined as at least 10 of 12 serotypes (or >83% of serotypes with data) achieving postvaccination serotype-specific immunoglobulin G ≥0.35 µg/mL and ≥4-fold rise, compared to prevaccination at 1 and 12 months. RESULTS: One hundred eighteen children were recruited. Only 12.8% (5/39; 95% confidence interval [CI], 4.3%-27.4%) of patients vaccinated during maintenance (group 1) achieved a protective response at 1 month postvaccination and none had a protective response at 12 months. For group 2 patients, 59.5% (22/37; 95% CI, 42.1%-75.3%) achieved a response at 1 month and 37.9% (11/29; 95% CI, 20.7%-57.7%) maintained immunity at 12 months. For group 3 patients, 56.8% (21/37; 95% CI, 39.5%-72.9%) achieved a protective response at 1 month and 43.3% (13/30; 95% CI, 25.5%-62.6%) maintained immunity at 12 months. CONCLUSIONS: This study demonstrated that the earliest time point at which protective immunity can be achieved in children with ALL is on completion of chemotherapy. This is earlier than current recommendations and may improve protection during a period when children are most susceptible to infection. CLINICAL TRIALS REGISTRATION: EudraCT 2009-011587-11.

PEPtalk2: results of a pilot randomised controlled trial to compare VZIG and aciclovir as postexposure prophylaxis (PEP) against chickenpox in children with cancer.

OBJECTIVE: To determine the likely rate of patient randomisation and to facilitate sample size calculation for a full-scale phase III trial of varicella zoster immunoglobulin (VZIG) and aciclovir as postexposure prophylaxis against chickenpox in children with cancer. DESIGN: Multicentre pilot randomised controlled trial of VZIG and oral aciclovir. SETTING: England, UK. PATIENTS: Children under 16 years of age with a diagnosis of cancer: currently or within 6 months of receiving cancer treatment and with negative varicella zoster virus (VZV) serostatus at diagnosis or within the last 3 months. INTERVENTIONS: Study participants who have a significant VZV exposure were randomised to receive PEP in the form of VZIG or aciclovir after the exposure. MAIN OUTCOME MEASURES: Number of patients registered and randomised within 12 months of the trial opening to recruitment and incidence of breakthrough varicella. RESULTS: The study opened in six sites over a 13-month period. 482 patients were screened for eligibility, 32 patients were registered and 3 patients were randomised following VZV exposure. All three were randomised to receive aciclovir and there were no cases of breakthrough varicella. CONCLUSIONS: Given the limited recruitment to the PEPtalk2 pilot, it is unlikely that the necessary sample size would be achievable using this strategy in a full-scale trial. The study identified factors that could be used to modify the design of a definitive trial but other options for defining the best means to protect such children against VZV should be explored. TRIAL REGISTRATION NUMBER: ISRCTN48257441, EudraCT number: 2013-001332-22, sponsor: University of Birmingham.

Varicella zoster immune status in children treated for acute leukemia.

Children treated for acute leukemia are at increased risk of severe infection with varicella zoster virus (VZV). We studied the VZV sero-status of children with acute leukemia prior to starting chemotherapy and after completion of chemotherapy. VZV sero-status was assessed using time resolved fluorescence immunoassay (TRFIA) before starting treatment and 6 months after completion of treatment. Prior to starting treatment for acute leukemia, a significant proportion of children (35%) are VZV seronegative. On completion of treatment most patients maintained protective VZV antibody levels; however, 35% had reduced/loss VZV antibody to a level considered non-protective and susceptible to VZV infection.

Serotype-specific pneumococcal antibody concentrations in children treated for acute leukaemia.

Children treated for acute leukaemia are at increased risk of infection with Streptococcus pneumoniae. The basis for this may include low levels of pneumococcal antibody but this has not been well studied. The authors measured serotype-specific pneumococcal IgG antibody concentrations in children treated for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) ≥6 months after completion of standard-dose chemotherapy. Pneumococcal serotype-specific IgG antibody concentrations were low. None of the subjects had protective concentrations against all the heptavalent-pneumococcal conjugate vaccine serotypes. There was no significant difference in antibody concentrations between subjects with ALL and AML (p≥0.05). Children treated for ALL and AML generally have non-protective antibody concentrations against S pneumoniae. There is significant morbidity associated with pneumococcal disease in this patient group and strategies for vaccination are required.

Immunisation practices of paediatric oncology and shared care oncology consultants: a United Kingdom survey.

BACKGROUND: In March 2002, the Royal College of Paediatrics and Child Health (RCPCH) introduced guidelines for re-immunisation of children after completion of standard-dose chemotherapy and after haematopoietic stem cell transplant (HSCT). AIMS: To ascertain whether these guidelines form standard unit policy by undertaking a survey of UK paediatric principal treatment centre (PTC) consultants and shared care (SC) consultants. PROCEDURES: In October 2008, a link to an on-line anonymised survey was sent by e-mail to all UK PTC consultants in Children's Cancer and Leukaemia Group (CCLG) centres and to SC consultants linked to eight of these centres. RESULTS: Responses were received from 55 PTC consultants (representing all 21 CCLG centres) and 54 SC consultants. In accordance with the RCPCH guidelines, most PTC and SC consultants recommend initiating re-immunisation at 6 months after completion of standard-dose chemotherapy (99/105, 94.3%). Re-immunisation at the recommended time after HSCT for each transplant type was reported by 93-100% of respondents. Pneumococcal conjugate vaccine (PCV) was recommended after chemotherapy by 58.3% (35/60) of respondents and by 51.7% (30/58) after HSCT. There were distinct differences between PTC and SC consultants in their choice of varicella (VZV) post-exposure prophylaxis. CONCLUSIONS: There is a high level of stated compliance with RCPCH guidelines. Recommendations for PCV after chemotherapy and HSCT were lower than expected. This may reflect the absence of specific guidelines after chemotherapy but not in HSCT patients where guidelines do exist. Variation in VZV post-exposure prophylaxis suggests further studies are required.

Hereditary leiomyomatosis and renal cell carcinoma: very early diagnosis of renal cancer in a paediatric patient.

Hereditary leiomyomatosis and renal cell cancer is a hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and renal cancer. Previous reports have stressed the aggressiveness of the renal tumours, often with early metastasis, despite small primary tumour size. Almost all the previously reported patients were adults, and different studies showed variability in penetrance for the renal tumours. We report a patient in whom renal cancer was detected at the age of 11 years at his first routine screening imaging after he was found to carry a fumarate hydratase gene mutation (c.1189G > A) transmitted from his mother. This report serves to emphasize the need to improve guidelines for screening of at risk individuals, including the necessity for predictive genetic testing and early institution of tumour surveillance in childhood.

Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation.

Most children with cancer are immunocompromised during therapy and for a variable period after completion of therapy. They are at an increased risk of infections, including vaccine-preventable infections. There is a reduction in immunity to vaccine-preventable diseases after completion of standard-dose chemotherapy and after hematopoietic stem cell transplant. It is important to protect these children against vaccine-preventable diseases by reimmunization.

Revaccination with measles, tetanus, poliovirus, Haemophilus influenzae type B, meningococcus C, and pneumococcus vaccines in children after hematopoietic stem cell transplantation.

BACKGROUND: There is a decrease in antibody levels after hematopoietic stem cell transplant (HSCT), and such patients may be at increased risk of acquiring vaccine-preventable infection. A simple and validated revaccination schedule is required. The aim of this study was to evaluate the immunogenicity of a revaccination schedule for pediatric HSCT recipients. METHODS: Thirty-eight children (age, 1-18 years) who had undergone autologous or allogeneic HSCT for malignant diseases were recruited. All children received vaccinations in accordance with a predefined schedule. Antibody concentrations were measured before and 2-4 weeks after vaccination against tetanus; Haemophilus influenzae type b (Hib); meningococcus C; measles; poliovirus serotypes 1, 2, and 3; and 9 pneumococcus serotypes. RESULTS: Before vaccination, protective antibody levels were found for tetanus in 95% of patients (geometric mean concentration [GMC], 0.07 IU/mL; 95% CI, 0.05-0.1 IU/mL), for Hib in 63% (GMC, 0.34 microg/mL; 95% CI, 0.21-0.57 microg/mL), for measles in 60% (GMC, 102 mIU/mL; 95% CI, 41-253 mIU/mL), for meningococcus C in 11% (geometric mean titer [GMT], 1:4; 95% CI, 1:2-1:8.4), for all 3 poliovirus serotypes in 29%, and for all 9 pneumococcal serotypes in 0%. Vaccination resulted in a significant increase (P < or = .05) in antibody levels to each vaccine antigen studied, with 100% of patients achieving protection against tetanus (GMC, 2.2 IU/mL; 95% CI, 1.8-2.7 IU/mL), 100% achieving protection against Hib (GMC, 8.4 microg/mL; 95% CI, 7.6-9.3 microg/mL), 100% achieving protection against measles (GMC, 2435 mIU/mL; 95% CI, 1724-3439 mIU/mL), 100% achieving protection against meningococcus C (GMT, 1:5706; 95% CI, 1:3510-1:9272), 92% achieving protection against the 3 poliovirus serotypes, and > or = 80% achieving protection against each of the heptavalent pneumococcal conjugate vaccine-associated serotypes. No factors relevant to age, underlying disease, or treatment type were found to significantly influence responses. CONCLUSION: Revaccination of pediatric HSCT recipients in accordance with this revaccination schedule provides a high level of protection against these vaccine-preventable diseases.

Revaccination of children after completion of standard chemotherapy for acute leukemia.

BACKGROUND: After the treatment of patients with acute leukemia, there is a decrease in vaccine-specific antibody and an increased susceptibility to certain vaccine-preventable diseases. A simple revaccination schedule is warranted. METHOD: Fifty-nine children (age, 1-18 years) who had completed standard chemotherapy in accordance with Medical Research Council of United Kingdom protocols were recruited. All children received a single dose of Haemophilus influenzae type b (Hib), tetanus, diphtheria, acellular pertussis, meningococcus C, polio, measles, mumps, and rubella vaccines > or = 6 months after completion of treatment. Antibody concentrations were measured before vaccination and 2-4 weeks and 12 months after vaccination. RESULTS: Prevaccination antibody levels were protective for all patients for tetanus (geometric mean concentration [GMC], 0.13 IU/mL; 95% CI, 0.1-0.17 IU/mL), for 87% for Hib (GMC, 0.5 microg/mL; 95% CI, 0.37-0.74 microg/mL), for 71% for measles (GMC, 301 mIU/mL; 95% CI, 163-557 mIU/mL), for 12% for meningococcus C (geometric mean titer [GMT], 1:2.9; 95% CI, 1:2.2 to 1:3.9), and for 11% for all 3 poliovirus serotypes. Revaccination resulted in a significant increase in levels of antibody to each vaccine antigen, with 100% of patients achieving optimal antitetanus antibody concentrations (defined as > 0.1 IU/mL; 1.5 IU/mL; 95% CI, 1.1-2.1 IU/mL), 93% achieving optimal antibody concentrations to Hib (defined as > 1.0 microg/mL; 6.5 microg/mL; 95% CI, 5.1-8.2 microg/mL), 94% achieving optimal antibody concentrations to measles (defined as > or = 120 mIU/mL; 2720 mIU/mL; 95% CI, 1423-5198 mIU/mL), 96% achieving optimal antibody concentrations to meningococcus C (defined as > or = 1:8; 1:1000; 95% CI, 1:483-1:2064), and 85% achieving optimal antibody concentrations to all the 3 poliovirus serotypes (defined as > or = 1:8). For the majority of subjects, protection persisted for at least 12 months after vaccination. CONCLUSION: Revaccination of children after standard chemotherapy is important, and protection can be achieved in the majority of these children using a simple schedule of 1 vaccine dose at 6 months after completion of leukemia therapy.

Cytomegalovirus reactivation in pediatric hemopoietic progenitors transplant: a retrospective study on the risk factors and the efficacy of treatment.

Cytomegalovirus (CMV) disease is an important infectious complication after allogeneic hemopoietic progenitors transplant (HPT), but few data are available in children. To investigate the factors influencing CMV reactivation, subsequent relapses of positive antigenemia, and the development of organ disease in children, the authors retrospectively analyzed 108 children who received allogeneic HPT for malignant conditions at one center. Of these, 41 were CMV serology positive (donor or recipient) before HPT. All those with CMV-positive serology received high-dose acyclovir in conjunction with weekly CMV phosphoprotein-pp65 antigen monitoring of the peripheral blood during the first 3 months. Those with CMV reactivation (positive antigenemia) received preemptive treatment with ganciclovir and/or foscarnet to prevent CMV disease. The incidence of positive antigenemia in this cohort was 41.5% at a mean of 44 +/- 31.6 days after HPT. Two patients (4.9%) subsequently developed late CMV disease. Recipient CMV status was significantly (P = 0.0001) more relevant to reactivation than donor status. Reactivations were significantly more common in single recipient seropositive than double (donor and recipient) positive pairs (P = 0.05). Reactivations were significantly more common in recipients of unrelated donor grafts than matched-related donor grafts (P = 0.025). Reactivations also occurred significantly more in T-cell-depleted graft recipients (P = 0.004) than recipients of unmanipulated grafts. The subsequent development of disease was more common in a CMV-seropositive recipient receiving a CMV-seronegative, T-cell-depleted, unrelated donor graft, and after transplantation receiving treatment for acute graft-versus-host disease. Patients with identified high risk factors for CMV reactivation and disease should be monitored by CMV PCR, and early preemptive treatment should be instigated to prevent the development of disease.

Varicella-zoster reactivation in a patient receiving routine revaccinations after an allogeneic hemopoietic progenitors transplant.

Primary varicella-zoster virus (VZV) infection and herpes zoster are important infectious complications after an allogeneic hemopoietic progenitors transplant (HPT). The authors describe a girl with second relapse of acute lymphoblastic leukemia who received an HPT at age 13 years. Two years after the HPT she started a revaccination program of routine childhood vaccines. With each course of vaccines she developed herpes zoster of the C6 dermatome, initially with the rash and later zoster sine herpete. The vaccinations appear to have triggered VZV reactivation by vaccine-induced immunomodulation in this HPT recipient.

High-dose granulocyte colony-stimulating factor mobilizes a higher proportion of early CD34(+) CD33(-) hemopoietic progenitors in children receiving treatment for solid tumors.

A relationship between dose of granulocyte colony-stimulating factor (G-CSF) and maturational stage of the progenitors mobilized in healthy adult donors has been suggested. In this study we characterize the progenitors mobilized by 2 different dosages of G-CSF in children receiving autologous grafts after intensive treatment for solid tumors.