Immune reconstitution after childhood leukemia. Aspects on immunizations and effects of Ara-C on the innate immune system

Abstract

Children with acute lymphoblastic leukemia (ALL) can be cured with cytotoxic chemotherapy, but myelosuppression and immunosuppression are major side effects causing morbidity and even mortality from infections. Vaccinations with diphtheria toxoid (DT), tetanus toxoid (TT) and protein conjugated Haemophilus influenzae type B (Hib) capsular polysaccharide were used to investigate the adaptive immune system in a controlled study of 31 children after treatment for ALL. Subprotective antibody levels were found in 83% of the patients against diphtheria and 67% against tetanus, whereas all had protective levels of Hib antibodies. All standard and intermediate risk patients had protective antibody levels after immunization. The memory response was weak in the high risk (HR) group, with subprotective antibody levels in a substantial proportion after immunization. Antibody avidity after immunization was low for anti-TT, but not for anti-Hib, in the HR group. The poor antibody production in the HR group correlated to low numbers of specific antibody secreting cells after immunization. No difference in the immune response was detected between patients vaccinated at one month (N=12) or six months (N=19) after treatment. To examine immune reconstitution after childhood ALL, lymphocyte populations and in vitro function of T and B cells was measured in the vaccine recipients. At 6 months after treatment T cells were subnormal due to low CD4+ and CD4+45RA+ T cells. During reconstitution the CD5+ B cells were increased, most marked in the HR group. These findings clearly suggest a relationship between treatment intensity and immunosuppression in children with ALL, which should influence the policy for immunizations. Inactivated vaccines are effective in patients from the lower risk group already at 1 month after treatment. The effect of repeated immunizations after 6 months in the HR group should be examined.Ara-C is an important, but highly myelosuppressive drug for ALL. To investigate the inflammatory reaction named the Ara-C syndrome a retrospective study of 57 patients in first complete remission (ALL=49, NHL=8) treated with 169 courses of high dose ara-C (HDAC) was performed. Ara-C fever occurred in 113/169 (67%) of the courses, and was associated with elevated plasma levels of the inflammation markers CRP and procalcitonin. An association between fever and release of proinflammatory cytokines (TNF-alpha, IL-6 and IFN-gamma) was found. This was counterbalanced by elevations of the anti-inflammatory cytokines IL1-ra and IL-10. The syndrome was self limiting, but could be inhibited by administration of corticosteroids. Myelosuppression, including lymphopenia, was profound after HDAC, and neutropenic fever occurred after 55% of the courses. The incidence of viridans streptococcal sepsis was low (2/169) and no mortality occurred, despite that 93% of all HDAC was administered without the use of colony stimulating factors. This study demonstrates that ara-C has strong effects on the innate immune system leading to an exceptionally high incidence of both drug fever and infections.