Derry Ridgway

Active Immunization of Children with Leukemia and Other Malignancies

Active immunization against measles, Haemophilus influenza B, tetanus, diphtheria, hepatitis B, influenza, poliomyelitis, and, when indicated varicella and pneumococcus induces long-lasting immunologic protection in most healthy pediatric vaccine recipients. Among children receiving immunosuppressive therapy for cancer, possible early loss of specific immunity acquired from prior vaccination or disease, and likely diminished responsiveness to initial or booster vaccination must be considered. In addition, the safety of vaccine administration requires separate study in this population. Published evidence demonstrates preservation of vaccine-induced antibody titers against tetanus, diphtheria, poliomyelitis and (in children treated for lymphoma) pneumococcus. In contrast, prior immunity to varicella, influenza, and hepatitis B (when naturally acquired), and measles (acquired by vaccination) is compromised during and/or after antineoplastic therapy. Studies of immunologic protection acquired by prior vaccination against hepatitis B, varicella, and H influenza have not been published. The safety of administering toxoids and inactivated vaccines in this population is well documented. In contrast, morbidity must be expected if live attenuated vaccines (oral polio vaccine, attenuated measles vaccine or attenuated varicella vaccine) are administered to children receiving anti-cancer therapy. The risks of using live vaccines should be measured against demonstrable benefits in any vaccine program. The response to initial or booster immunizations against tetanus and diphtheria are similar to those in healthy children. For all other immunizations reviewed, responsiveness is diminished during periods of chemotherapy, more strikingly in children treated for leukemia than for solid tumors. Antibody responses to these vaccines range from slightly blunted (in the case of H influenza B) to marginal (influenza) or completely useless (pneumococcus and hepatitis B in children treated for leukemia).

Successful bone marrow transplantation with split lymphoid chimerism in DiGeorge syndrome

A female infant with DiGeorge syndrome associated with severe T-cell immunodeficiency underwent a successful bone marrow transplantation from her HLA-identical, mixed leukocyte culture-nonreactive brother at 5 months of age. Mature circulating T cells and mitogen-induced proliferative responses were detectable at 10 days posttransplant, and by 8 months posttransplant functional T- and B-cell reconstitution was documented by normal responses to mitogens and normal levels of serum immunoglobulins as well asin vitro andin vivo T-cell reactivity to specific antigens and production of specific antibody to T cell-dependent antigensin vivo. Phytohemagglutinin-induced interleukin-2 production and cell surface interleukin-2 receptor expression improved posttransplant, with normal production values observed by 8 months posttransplant. Histologic examination of appendix and thoracic lymph node obtained 9 and 17 months posttransplant, respectively, revealed near-normal lymphoid architecture, with germinal center formation providing morphologic confirmation of reconstitution. Stable split lymphoid chimerism with T cells of donor origin and B cells remaining recipient in origin was documented by sex chromosome analysis. Two years posttransplant the subject remains free of serious infections. In conclusion, this case indicates that bone marrow transplantation can produce peripheral immunoreconstitution without need for significant thymic influence, most likely by providing a source of postthymic T cells, and that bone marrow transplantation should be considered a therapeutic option in patients with DiGeorge syndrome associated with severe T-cell deficiency.

Attenuation of asparaginase-induced hyperglycemia after substitution of the Erwinia carotovora for the Escherichia coli enzyme preparation.

L‐asparaginase, an enzyme with established antileukemic activity, increases the induction rate and duration of remission of acute lymphoblastic leukemia when added to vincristine and prednisone for induction therapy. Enzymes derived from two different bacterial sources (Escherichia coli and Erwinia carotovora) are in common use. These enzymes may be associated with toxic reactions of differing frequency and severity. Specifically, the complication of enzyme‐induced hyperglycemia may be seen more frequently after exposure to the E, coli product. The authors present two patients in whom it was necessary to substitute the Erwinia enzyme for the E. coli enzyme because of the occurrence of severe allergic reactions to the E. coli enzyme. Hyperglycemia induced by the first product improved after the substitution, suggesting that the Erwinia enzyme may be less diabetogenic that the E. coli enzyme.

Childhood cancer among the polynesian population

From June 1981 through June 1989, 95 Polynesian children were seen for initial care of malignancy at the Princess Mary Hospital for Children (PMHC). The incidence of malignancy in the Polynesian populations served, the histology of the malignancies, and the outcome of therapy were reviewed and compared with 185 non‐Polynesian (non‐P) patients seen during the same period. Incidence figures for Polynesians and non‐P were similar, but histologic patterns differed, showing an increased occurrence of leukemia, particularly nonlymphoblastic leukemia, an increased occurrence of bone tumors, and a decreased incidence of central nervous system tumors for Polynesians. Survival for Polynesian children with acute lymphoblastic leukemia was worse than for non‐P. Survival in all other disease categories was similar.

Enhanced lymphocyte response to PHA among leukemia patients taking oral lithium carbonate

Seven children receiving maintenance therapy for acute lymphoblastic leukemia (in remission) were given oral lithium carbonate for 12 weeks. Hematologic values, serum immunoglobulin levels, and responsiveness of peripheral blood mononuclear cells to mitogen stimulation were studied during the lithium treatment period, and compared to measurements made during a 12-week period when no lithium was administered (children served as their own controls). Changes attributable to treatment with lithium carbonate included increases in total white blood cell count, circulating neutrophil count, and response to phytohemagglutinin-P. No important toxicity to lithium carbonate was observed.

Elevated production of interleukin-2 by lymphocytes from children with acute leukemia.

Abnormalities of the production of interleukin-2 (IL-2) may play an important role in the immunologic dysfunction observed in pediatric leukemia patients. For an evaluation of the ability of lymphocytes from leukemic children to produce this cytokine, the production of IL-2 by mitogen-stimulated peripheral blood mononuclear cells was determined in children with acute leukemia at the time of diagnosis, during clinical remission, and at the time of relapse. Of 16 patients, 11 (69%) with either acute lymphoblastic leukemia or acute nonlymphoblastic leukemia at the time of diagnosis had IL-2 production levels above the highest level observed in control subjects, and all but one had values above the control mean. Three of five treated patients had elevated IL-2 production at the time of bone marrow relapse. In addition, of 37 patients examined during clinical remission (both during chemotherapy and after the completion of maintenance chemotherapy), five had IL-2 production values above the control range and four of these five patients subsequently had relapses, compared with only one relapse in the remaining 32 patients with normal or below-normal levels of IL-2 production. These results demonstrate an increased ability to produce IL-2 by many patients with acute leukemia, both at the time of diagnosis and at relapse. Elevated IL-2 production may represent an immunologic response to leukemic cells and in some patients may provide a marker for persistent leukemia.

Indomethacin-Sensitive Monocyte Killing Defect in a Child with Disseminated Atypical Mycobacterial Disease

A child with disseminated disease due toMycobacterium avium had progressive disease in spite of 4.5 years of therapy with multiple antimicrobial agents selected on the basis ofin vitro sensitivity testing of her organism. A defect in monocyte bactericidal activity was detected which was correctedin vitro by exposure of the patients monocytes to indomethacin and normal serum. Indomethacin therapy resulted in normalization of monocyte bactericidal activity and striking, albeit temporary, clinical improvement.

The effects of thymic epithelial monolayer-conditioned medium on suppressor cell function following chemotherapy in pediatric patients

SummaryHuman thymic epithelial monolayer-conditioned medium (TEM-CM) enhanced concanavalin A (ConA)-induced suppressor T-lymphocyte activity in 15 of 17 studies of fractionated light-density bone marrow mononuclear cells (LD-BMMC) obtained from pediatric cancer patients within 7 days of chemotherapy (P<0.001). However, TEM-CM depressed ConA-induced suppressor T-lymphocyte activity in 14 of 18 studies of LD-BMMC obtained from patients who had received their chemotherapy 14–21 days previously (P<0.05). In studies of LD-BMMC from normal subjects, TEM-CM did not show any significant effect on suppressor cell activity, nor did TEM-CM significantly affect spontaneous suppressor cell activity in patients or normals. The effect of direct culture on thymic epithelial monolayers was equivalent to the effect of TEM-CM in both ConA-induced and spontaneous suppressor cell assays. These data demonstrate thymic factor-mediated changes in suppressor T-cell activity of pediatric cancer patients and suggest a postchemotherapy alteration in the bone marrow population of inducible prethymic T cells.

EFFECT OF MAINTENANCE CHEMOTHERAPY (C) FOR ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ON INTERLEUKIN-2 (IL-2) PRODUCTION, RESPONSE AND RECEPTOR EXPRESSION

This study was undertaken to define both the acute and long-term effects of C on the IL-2 system. 10 children with ALL receiving standard C for 6-36 mos, 11 children with All off all C for 2-80 mos and 15 age-matched controls were studied. Responsiveness to IL-2 was determined by culturing activated T cells with human recombinant IL-2 with proliferation estimated by 3H-TdR incorporation. IL-2 production was quantitated in culture supernatants from phytohemagglutinin(PHA)-stimulated mononuclear cells(MNC). IL-2 receptor(IL-2R)expression was quantitated on PHA-stimulated MNC.In conclusion, these results demonstrate that children with ALL receiving C have a significantly depressed IL-2 system. These results also show that although cessation of C allowed IL-2 responsiveness to normalize, the defects in IL-2 production and IL-2R expression persisted, suggesting that a substantial therapy-induced immunodeficiency may be among the late effects present in long-term survivors of ALL.