Newborn screening for hemoglobinopathies in Colorado. The first 10 years.

In Colorado, newborn screening for hemoglobinopathies by cellulose acetate and citrate agar electrophoresis of dried capillary blood spots was established in 1979. We reviewed the results of screening 528,711 infants through 1988. Forty-seven infants with sickle cell diseases and 27 infants with other hemoglobin diseases were identified. The initial screening failed to detect sickle cell anemia in 4 infants, but the hemoglobinopathy in 3 of these infants was diagnosed correctly by routine retesting of those with suspected sickle cell trait. A total of 47 infants with sickle cell diseases were followed through September 1989. There was no mortality among these infants. The screening test identified 3779 infants (1:140 births) with a suspected hemoglobin trait; confirmatory retesting was obtained in 53%. The results of our experience confirm the value of newborn screening for hemoglobinopathies but suggest that a more sensitive test would improve the program.

Intranasal administration of deferoxamine to iron overloaded patients.

We examined the effect of intranasal administration of deferoxamine on iron excretion in seven patients with iron overload secondary to chronic transfusion therapy. Deferoxamine was administered in doses of 0.75 to 3.0 gm given over 12 hours in a variety of dosing schedules. There was a probable, though not significant, dose response relationship between the amount of iron excreted and the dose administered. The amount of iron excreted was 10%-15% of that obtained using the same dosage of deferoxamine given by the subcutaneous route over the same time period. Hourly administration was more effective than less frequent administration. Addition of taurodeoxycholate to deferoxamine did not increase its absorption as measured by the levels of iron excretion. Side effects were few and consisted mainly of mild nasal irritation and a bad taste in the mouth. Nasal administration of deferoxamine may be a useful adjunct to iron chelation in patients receiving chronic transfusion therapy, particularly in those who are noncompliant with parenteral means of administration.

Intermittent combination chemotherapy with or without bacillus Calmette-Guérin for treatment of acute lymphoblastic leukemia of childhood.

Seventy-four children ranging in age from 6 months to 17.5 years with acute lymphoblastic leukemia newly diagnosed between 1976 and 1979 were entered on a study incorporating intermittent chemotherapy with or without the addition of bacillus Calmette-Guérin (BCG). The chemotherapy program consisted of induction with vincristine, dexamethasone, and intrathecal methotrexate, intensification with adriamycin and asparaginase, central nervous system treatment with cranial irradiation and intrathecal methotrexate, and continuation treatment with 5-day courses of combination chemotherapy administered every three weeks. The first phase of continuation therapy incorporated vincristine, adriamycin, 6-mercaptopurine, and dexamethasone. In the second phase, oral methotrexate was substituted for the adriamycin in non-T-cell patients; in T-cell patients, cytosine arabinoside or cyclophosphamide and methotrexate in alternating cycles were substituted for the adriamycin and asparaginase was added. Total duration of therapy was approximately 2.5 years. Connaught BCG was administered by Heaf gun on days 8 and 15 of each 3-week cycle for the first 8 months of treatment in approximately one-third of the patients. Actuarial disease-free survival with a median follow-up of 59 months shows no difference in outcome between the BCG and non-BCG poor-risk patients. However, there is an improvement in disease-free survival of BCG-treated good- and average-risk girls (P = 0.04). While patients were actively receiving BCG there was also a trend toward the development of fewer significant infections than when patients were not receiving BCG (P = 0.85). Toxicities from BCG administration included satellite rashes, local tenderness, lymphadenopathy, secondary infection, and residual scars. Overall disease-free survival by actuarial analysis is 60% at 6 years; for patients with unfavorable prognostic features it is 40%. In this trial the addition of BCG prolonged the disease-free survival of girls with good- and average-risk prognostic features and also may have decreased the susceptibility to infection while it was being administered. However, the benefit does not appear sufficient to warrant its routine use, especially in view of the toxicities encountered.

Probable graft-vs-graft reaction in an infant after exchange transfusion and marrow transplantation.

A newborn with graft-vs-host (GVH) disease following an exchange transfusion was treated by attempting to eradicate the incompatible graft and to reconstitute the child hematologically and immunologically with a bone marrow transplant. The patient was a female term infant (blood group B, Rh+ Coombs test positive) who received a one-unit group O, Rh- exchange transfusion from an unrelated female donor for hyperbilirubinemia due to ABO incompatibility on day 2. Signs of acute GVH disease began on day 8 and the clinical diagnosis was supported by skin biopsy. With antithymocyte globulin and high dose dexamethasone, the GVH reaction improved somewhat. Cyclophosphamide, 200 mg/kg total dose, was given over four days followed by a marrow graft from a brother who was HLA-A, B identical, and probably also D locus compatible in mixed lymphocyte culture. All signs of GVH resolved with cyclophosphamide treatment and hematologic reconstitution was evident by 14 days after transplant. Two weeks later the GVH reaction and aplastic anemia recurred and Y chromatin was detected in only 6% of marrow cells. The infant died on day 80. Autopsy showed disseminated candidiasis, disseminated cytomegalovirus infection, thymic dysplasia, hypoplastic marrow, and other histopathologic changes consistent with GVH disease. The persistence of female cells in blood and bone marrow and the destruction of the reconstituted marrow suggest that the original incompatible transfusion-derived graft was not eliminated and that it ultimately rejected the histocompatible marrow graft.

Effect of subcutaneous deferoxamine and oral vitamin C on iron excretion in congenital hypoplastic anemia and refractory anemia associated with the 5q-syndrome.

Chronic refractory anemia associated with congenital hypoplastic anemia (CHA, Blackfan-Diamond syndrome) and with the 5q-syndrome may require chronic transfusion therapy to sustain life. Hemosiderosis and death from chronic iron overload may result from such a program. The effect of subcutaneous (SC) deferoxamine (DF) and supplemental oral vitamin C (vit. C) on urinary iron excretion was studied in two patients with congenital hypoplastic anemia and one patient with 5q-syndrome. In the two patients with CHA, urinary iron excretion in response to DF given SC over 24 hours was comparable to the results following intravenous (I.V.) administration. Both of these cases had low levels of plasma ascorbate on initial evaluation and excreted more iron in response to two different doses of DF after they had received supplemental vit C and their stores were repleted. Significant iron excretion occurred in all three patients for 12 hours during the SC infusion of DF and for 12 hours after the end of the infusion. In all three patients, increasing the dose of DF up to 3-4 g given SC over 12 hours resulted in a linear increase in iron excretion. Once normal body stores of ascorbate were achieved by oral supplementation, increasing doses of vit C did not appear to cause a further increment in iron excretion. DF administered by a slow SC infusion appears to be an effective approach to iron overload in patients with refractory anemia and hemosiderosis secondary to chronic transfusions. Only small amounts of supplemental vit. C necessary to sustain adequate body stores are required for optimal iron excretion.

Regression on oxymetholone-induced hepatic tumors after bone marrow transplantation in aplastic anemia.

Treatment of acquired aplastic anemia with androgens has been occasionally associated with the development of hepatic tumors. We have studied a 13-year-old boy with idiopathic aplastic anemia in whom oxymetholone treatment was associated with a partial hematological remission. Thirty-four months later, however, the patient developed multiple hepatic tumors. When oxymetholone therapy was discontinued, the aplastic anemia relapsed. He then underwent bone marrow transplantation from his HLA-A, B, and D-compatible sibling. This was followed by hematological and immunological reconstitution. The hepatic tumors underwent progressive regression after bone marrow transplantation. The patient is now 3 years post-bone marrow transplantation and is in complete remission of his aplastic anemia with no evidence of detectable liver tumors.

Remission of relapsed leukaemia during a graft-versus-host reaction. A "graft-versus-leukaemia reaction" in man?

Acute lymphoblastic leukaemic in two boys relapsed after engraftment of marrow from siblings identical at HLA A, B, and D loci but went into remission during subsequent graft-versus-host reactions without specific anti-leukaemia therapy. Later leukaemic relapse was primarily in extramedullary sites, with little or no involvement of bone-marrow, liver, or spleen. Cytogenetic studies in both cases showed that the relapsed leukaemic blasts were those of the recipients while marrow cells and blood lymphocytes detected during marrow remission originated from the female donors. Blood lymphocytes from one of the recepients kiled. 51Cr-labelled autologous lymphoblast. The prolonged bone-marrow remission in the face of active and even massive extramedullary leukaemia suggests a graft-versus-leukaemia reaction in these two patients.

Nine cases of sphingomyelin lipidosis, a new variant in Spanish-American Children. Juvenile variant of Niemann-Pick Disease with foamy and sea-blue histiocytes.

We describe nine Spanish-American children from five families with an unusual hereditary lipid storage disease. The family origins were in two small southern Colorado towns. The clinical course varied, but all of the children were found to bruise easily and to have splenomegaly, while most had hepatomegaly. Post-natal jaundice and hepatitis occurred in four. Impairment of vertical gaze and intellectual and neurologic deterioration occurred in most of the patients, with the onset of the disease, usually in childhood. The bone marrow in all patients examined contained both foamy and sea-blue histiocytes. Sphingomyelinase levels in skin fibroblast cultures were greatly decreased in seven of the eight cases evaluated. It is believed that these patients have a sphingomyelin lipidosis and represent a variant of the Niemann-Pick disease. Clinical and enzymatic findings are compared with those of other cases in the literature.

Establishment of erythropoiesis following bone marrow transplantation in a patient with congenital hypoplastic anemia (Diamond-Blackfan syndrome).

Marrow transplantation was attempted in a 13-yr-old boy with congenital hypoplastic anemia who had never responded to corticosteroid therapy. Prior to the transplant, he had received 238 transfusions, at least 12 of which were from his father. He was prepared for grafting with antilymphocyte globulin, procarbazine, and total body irradiation (1000 rads). The patient, whose red cells were Group B, then received marrow cells from his Group O, histocompatible, sister. Thereafter, reticulocytes, Group O erythrocytes, and female leukocytes appeared in the peripheral blood. Erythroid precursors were seen in the patient's marrow for the first time in his life, and all lacked fluorescent Y chromosomes. Dividing cells were all female. After initially progressing well, the patient developed interstitial pneumonia and died 55 days after the transplant. The successful erythroid graft suggested that this patient's failure to produce red blood cells was due to a defective stem cell rather than to a humoral defect, plasma inhibitor, or abnormal marrow microenvironment. It suggested further that sibling marrow may be engrafted in patients who have received multiple transfusions, even from a parent.