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Investigation of in vitro humoral immune responses and immunoregulatory properties of leukemic cell was carried out in 17 children with acute leukemia prior to therapy. Leukemias were of the non-T, non-B-cell type in 13 patients and of T-cell origin in four. Bone marrow and peripheral blood cells consisted of 24-96% lymphoblasts and were generally deficient in surface Ig-positive cells. Induction of Ig secreting cells in response to pokeweed mitogen was markedly decreased in marrow and peripheral mononuclear cell cultures of leukemic patients. Co-culture of leukemic cells with normal lymphocytes led to marked deviations from the expected Ig secreting-cell response of the cell mixtures. The predominant effect was enhancement, as was the case with eight non-T, non-B-cell and one T-cell leukemia samples. Suppression of the Ig secreting-cell response was observed in only three instances, two with non-T, non-B-cell and one with T-cell leukemia samples. These findings implicate non-T, non-B as well as more differentiated leukemic cells in having the potential for modifying Ig production by B cells.

In the natural history of Thalassemia Major (Thal) with hemochromatosis, problems of conduction become increasingly prevalent. Intracardiac conduction intervals were measured during cardiac catheterization in 12 patients with Thal aged 11-28 years (mean 20.4 years) and compared to those of 13 normal individuals aged 14-17 years (mean 15.5 years). In Thal, hemoglobin values were 10.9 ± 1.6 Gm% at the time of study. Five of the Thal group were receiving digoxin for supraventricular arrhythmia and none were in heart failure. Normal subjects had: PH 92.2 ± 15.1 msec; AH 69.6 ± 16.5 msec; PA 23.2 ± 6.1 msec; HV 43.7 ± 6.4 msec.Significant differences were noted in Thal patients in PH and AH intervals: PH 135.0±30.0 msec (p< 0.001); AH 107.9 ± 27.1 msec (p< 0.001). The PA time [26.8 ± 9.5 msec] and HV interval [38.0 ± 5.7 msec] were similar to normal. There were no differences in any parameters between Thal patients receiving or not receiving digoxin, but those receiving digoxin had slightly longer intervals for PH and AH: PH 143.0 ± 21.1 msec vs 130.0 ± 35.6 msec (p< 0.001 vs p< 0.02 compared to normal) and AH 118.0 ± 16.8 msec vs 100.7 ± 31.8 msec (p

Desferrioxamine (DF) has recently proven to be extremely efficacious in inducing iron excretion when administered as an IV or SC infusion. To determine appropriate IV drug doses for thalassemic children of different ages, we performed 17 dose-response studies on patients from 5 to 26 years old. Each child received 4 one-week courses of IV DF at doses of 20, 40, 60 and 80mg/kg. Three patients received SC DF by portable infusion pump at 20 mg/kg over 8 hours for one week and 16 hours another week. At 20 mg/kg, drug efficiency (urinary Iron excretion/theoretical maximum excretion) was 55% in the youngest group but fell rapidly as the dose was increased. In contrast, drug efficiency was 86% in patients over 11 years and dropped off slowly to 62% at 80 mg/kg. At the same dose, SC DF given over 8 hours was shown to be almost as effective as 16 hours SC and 24 hours IV DF, permitting over-night SC administration. Thus, drug dose and route of administration should be adjusted according to age and requirements.

Patients with homozygous B-thalassemia of ten have moderate to severe epistaxis and/or a petechial rash with normal platelet count, PT and PTT. For this reason we have studied platelet function (P1 F). Pre-transfusion evaluation included: Duke bleeding time (BT), PF3 release (Stypven), aggregation (epinephrine, ADP, collagen), PT, PTT and platelet count. PI F was abnormal in 13/30 patients(43%) studied: 10/13 had recurrent epistaxis and/or petechial rashes. 3 had minimal symptoms; 13/13 had abnormal aggregation with epinephrine, 10/13 with ADP, and 10/13 with collagen; only 1 also had slightly low PF3 release; BT was abnormal in 3/13. At time of study platelet count was normal in all, PT and PTT in most; none were receiving anti-aggregating drugs. Patients' platelets were isolated, washed by Ardlie buffer method, lysed and analyzed spectophotomet-rically for iron. No iron deposition in platelets was detected by this method. In other experiments, donor platelets were washed or gel-filtered to render them free of donor plasma; test plasma was then added to platelets and platelet aggregation assays were performed. Normal donor platelets were abnormal when tested in plasma from patients with abnormal P1 F; platelets from 3 patients with abnormal P1 F functioned normally in normal plasma but abnormally in “abnormal” plasma. Abnormalities of platelet aggregation are detectable in 1/2 symptomatic patients. Our data suggest that the P1 F abnormalities detected in β-thalassemia may be due to a plasma Inhibitor, rather than an intrinsic platelet defect.

Since Feb. 1975, 883 previously untreated children with ALL have been entered on a protocol designed to evaluate prognostic factors which influence induction, remission duration and survival and to identify subsets of patients with high risk of early failure. Complete marrow remission (M1) rates ranged between 91-95%. The combination of older age (>10yrs), high initial WBC (>20,000/μ1) and low serum IgG are associated with a significantly lower M1 rate. Skin test response to recall antigens, serum inhibition of blastogenesis, HLA type or PAS positivity were not prognostic of induction or remission duration. Patients in poor prognostic group (any age, initial WBC>50,000/μ1) with L1 blasts (FAB classification, Br.J.Hem 33:451,1976) had higher M1 rate than those with L2 blasts (80 vs 67%). Using the Mantel-Peto-Cox Chi square statistic for life table data, significant factors associated with poor prognosis include: WBC>20,000/μ1; age >7yrs; M3 marrow day 14; CNS disease at diagnosis; L2 lymphoblasts; decreased serum IgG and IgA; black race. Mediastinal mass is not an independent factor. None of 41 patients in low risk group (age 3-7yrs, WBC

F/N is a frequent complication of treatment in a child with cancer; management is controversial and variable. We surveyed 70 pediatric oncology programs (POP) to determine the prevalent approach to this problem. Of those surveyed, 80% responded representing an annual accrual of about 5000 new oncology patients (pts). Analysis of the data showed that criteria for antibiotics (Ab) are temperature between 38°C and 38.5°Ca and absolute neutrophil count (ANC) 500. However, if the ANC remains 500-1000 regardless of duration) even in the absence of fever or DI. Only 9% treat for 3 days, Duration of Ab for pts with DI averages 103 (range 7-14) depending on the site if ANC >500. Thus most POP treat pts with F/N as if infected whether inf is documented or not. In neutropenic pts on Ab with persistent fever but no source 62% start amphotericin (ampho) 7d and 19% after >7d. 11% have no specific indications and 8% don't use ampho. After an afebrile period 55% do not treat recurrence of fever with ampho. Once started duration of treatment with ampho is extremely variable. There was good agreement among POP for F/N occurring during administration of blood product or chemotherapy known to cause fever. 65% culture and observe only; 16% treat with Ab until cultures are negative; 11% wait until ANC >500. On the use of trimethoprim/sulfamethoxazole (TM) or mycostatin (My) prophylactically during induction/consolidation: 30% do not use TM even for leukemia and 75% do not use My at all. In conclusion, although there are published guidelines and informal discussion of treatment of F/N, this study documents the acceptance of and adherence to these recommendations and defines the currently practiced standards of care. It defines fruitful areas for further clinical investigation.

The heterogeneous disorder, CDA, is characterized by ineffective erythropoiesis and ultrastructural alterations of late erythroblasts. Three major types have been described: Type I with macrocytosis, Type II (HEMPAS) with abnormal RBC antigens,and Type III with gigantoblasts. Studies of RBC antigens, metabolism, lipids, ferrokinetics, in vitro erythroid colony formation, and globinchain synthesis were performed in a 15 year old male with atypical CDA. Ferrokinetics showed ineffective erythropoiesis, chromium survival was shortened, bone marrow revealed 25-35% 2-3 lobed late normoblasts, and electron microscopy showed dyserythropoiesis but no “double membranes” or internuclear bridges. Acidhemolysis tests with 20 ABO compatible sera were negative and hemolysis by anti-I, anti-i, or hemolytic anti-B was not increased. Activity of i matched that of fetal cells. Increased membrane phosphatidyl choline (36%, normal 29%) and decreased sphingomyelin (19%, normal 27%) were noted. The ratio of α and β chain synthesized by peripheral blood and BM RBC was normal; glycolytic intermediates and enzymes were normal except for pyruvatekinase. Erythroid colony formation in vitro was normal; dyserythropoiesis was not observed. The findings are compatible with CDA Type IV, a rare disorder with morphologic features of Type II but lacking abnormal serology. Attempts to apply distinctive ultrastructural features to CDA may be misleading.

Determination of the optimal duration of therapy and identification of patients (pts) at risk of relapsing after therapy is discontinuea are important strategies in ALL now that ≥50% of effectively-treated children are ≥3 year disease free sur vivqrs (DFS). Approximately 10-20% of pts sustain LR. Two CCSG studies, COG 141 and CCG 160 series were designed to evaluate the significance of clinical and biologic prognostic factors in determining outcome. In CCG 141, the early response to induction therapy as determined by the percentage orblasts in the day 14 bone marrow (dI4BM) aspirate is a highly significant, independent predictor of DPS. In addition the overall relapse rate, isolated BM relapse rate and death rate were significantly higher in pts with OTL (N=23, 9.7%) detected after 3 years DPS than in pts with negative biopsies (bx) (N=206, 86.9%), p 25%) BM ratings was 0.88, 1.78 and 2.02 respectively, (p0.0002). Other significant predictors of LR wer group (p0.0003) and initial WBC (p0.004). In conclusion, early response should be monitored closely and alternate induction regimens used for slow responders. At end therapy, the presence of OTL indicates significant, aggressive minimal residual disease requiring intervention and intensification of therapy.

In vitro semisolid agar culture has been used to characterize and predict relapse in myelold leukemias. We evaluated 5 children with ALL on the same drug regimen with sequential BM and CFC on day 0, 14, 28, and 83 or 138 to characterize the CFC in ALL and compare cytologic methods to CFC to predict chemotherapeutic effect and relapse. Feeder underlayers were prepared from 1×106 normal human WBC in 0.3% agar and McCoys media as a source of CSF; 2×106 nucleated marrow cells were overlayered. Colonies were counted at day 14 and compared to the peripheral blood absolute neutrophll count (ANC) and Giemsa stained BM. BM cellularity was ranked from 0–4 (3=normocellular). There was poor correlation between CFU-C and ANC. However, an increase in CFU-C was noted with impending remission induction as the BM was reconstituted with myelold precursors. This was most consistently noted when serial determinations were performed on an individual. In one patient no increase in CFU-C was noted despite cytologic evidence of remission; this patient subsequently relapsed. Serial assessment of CFU-C may be helpful in predicting relapse before morphological evidence on routine BM preparations, but does not help in predicting chemotherapeutically induced neutropenia.