Sanford L. Leikin

Prognostic Importance of Morphology (FAB Classification) in Childhood Acute Lymphoblastic Leukaemia (ALL)

Summary. The French‐American‐British (FAB) classification has been proposed as a useful and uniform method of defining morphologic subsets of acute leukaemias. As part of a prospective study designed to identify subsets of children with high risk of early relapse (CCG 141), submitted bone marrow slides from 765 of 883 patients entered on study were reviewed by two morphologists blinded as to prognostic factors and treatment regimen. L1, L2 and L3 acute lymphoblastic leukaemia (ALL) comprised 85·1%, 14·1% and 0·8%, respectively, of the total population. Children with > 25% L2 lymphoblasts had a significantly higher relapse rate and significantly poorer survival. Results of this study indicate that as a single variable, lymphoblast morphology is a very significant predictor of survival, haematologic remission, and complete continuous remission. Multivariate analyses show that lymphoblast morphology is again significant in determining duration of survival (P=0·048), and is of borderline statistical significance (P=0·089) in predicting length of complete continuous remission. The FAB classification, with minor modifications, is reproducible, useful, and prognostic in childhood ALL.

Lymphomatous presentation of childhood acute lymphoblastic leukemia a subgroup at high risk of early treatment failure

Multivariate analyses of the clinical course of 1537 children with acute lymphoblastic leukemia (ALL) identified a subgroup which experienced short remission duration and a high incidence of extramedullary relapse. The patients differed from other ALL patients by the presence at diagnosis of two or more of a constellation of clinical and laboratory features: organomegaly or mass disease, Erosette positivity, hemoglobin level greater than 10 g/dl, leukocyte count greater than 50,000/μl, male predominance, and older age. This type of presentation of ALL is referred to as the “lymphoma syndrome” (LS) since such patients exhibit a pattern of several clinical and laboratory features which were observed repeatedly but in differing combinations, and some of which clinically resemble lymphoma. A subsequent database from 2231 patients was analyzed. Patients with a mediastinal mass, massive splenomegaly, or massive adenopathy, alone or in combination, had a worse outcome when the patient also had either leukocytosis, E‐rosette‐positive lymphoblasts, or a normal or near normal hemoglobin (Hb) level at diagnosis. Similarly, the above three laboratory features alone or in combination did not predict less than 40% disease‐free survival (DFS) unless they were accompanied by at least one of the clinical features of mass disease. When at least one clinical feature and at least one laboratory feature were present, the overall DFS was 36% 6 years after diagnosis versus 64% for all other patients. The association of these features with poor prognosis remained significant after adjusting for the level of leukocyte count at diagnosis, age at diagnosis, and sex of the patients. Patients with this recurrent syndrome of features do not represent a homogeneous biologic entity but they constitute a subgroup of patients with ALL having a high risk of treatment failure using current therapies, including failure to achieve remission, early relapse, and increased frequency of relapse in extramedullary sites. They deserve early recognition at diagnosis and selection of treatment strategies appropriate for very high risk ALL.

Minors' assent or dissent to medical treatment

Summary It is clear that competency to consent requires a number of attributes and develops in children over time. It can be accelerated by factors such as education, training, and experience. An inverse relationship exists between behavior and perception of vulnerability to health problems among persons with a high degree of perceived internal control. There is also an inverse relationship between perceived internal control and perception of vulnerability to health problems in persons for whom health is salient. 22 These correlates indicate that efforts to heighten a persons perceived internal control and concern for health could potentiate positive health behavior in adults by encouraging perceived internal control among the young. To increase the minors perception of internal control, it may be the obligation of parents, as well as health providers, to establish a climate that encourages the development of those capabilities required for competency to consent and to grant autonomy to each minor individual with the attainment of those capabilities. During the minors dependency and vulnerability theconsent process can be flagrantly abused through deception, undue inducement, or coercion. It is our responsibility to intervene in the minors behalf in such instances. We must communicate with minors concerning medical needs in terms that can be understood. On the other hand, the psychological competencies that minors may possess are important determinants of their ability to conceptualize illness, to make decisions, and to act in their own behalf. Their capabilities and limitations should be borne in mind in relation to the informed consent process. Because of the wide variations in competence among individual children, it is important that a determination be made concerning the level of understanding and reasoning ability of each individual. Communication at that level will best enhance the minors participation in decision making and the informed consent process. As competencies develop, their participation should increase. The developmental psychological approach will provide autonomy to those individuals capable of assuming it, without denying protection to those who cannot.

Varying prednisone dosage in remission induction of previously untreated childhood leukemia.

Although prednisone has been effectively used to induce remission in acute leukemia, a controlled exploration of optimal dosage and of intermittent therapy has not been reported. Of 223 previously untreated children 86 received 2 mg/kg in three divided daily doses; 85 received 4 mg/kg in three divided daily doses; 28 received 8mg/kg every other day in a single dose and 24 received 16 mg/kg every fourth day in a single dose. Steroid side effects were minimal in intermittent therapy. The percentage of remissions on these two regimes, however, was significantly lower than on continuous therapy. Bone marrow remissions were found in 21% on 8 mg/kg every other day and 12% on 16 mg/kg every fourth day. Remission rates of 72% and 60%, respectively, were obtained on the 2mg/kg and 4 mg/kg regimens, indicating no significant difference between these two groups. Continuous prednisone therapy appears to be more effective than intermittent dosage regimens in inducing remission in acute childhood leukemia.

The impact of chemotherapy on advanced neuroblastoma. Survival of patients diagnosed in 1956, 1962, and 1966-68 in Children's Cancer Study Group A

Survival statistics from 50 children with disseminated neuroblastoma, treated according to two CCSGA protocols between 1966 and 1968, are compared to those collected by Sutow and associates for 1956 and 1962. Little improvement occurred in the median survival rates of the children in these groups. Survival at 24 months is 13, 22, and 13 per cent, respectively, for the three groups. The lack of improvement in the median survival rate following treatment with a combination of VCR and CPM is attributed to an initial response rate of less than 40 per cent in the treated patients. The survival of patients who did respond, when compared to those who did not, was twice as long (15 vs. 7 months). Clearly, improved chemotherapy or other modes of treatment are needed for patients with advanced neuroblastoma at the time of diagnosis.

Immune competence in congenital rubella: Lymphocyte transformation, delayed hypersensitivity, and response to vaccination

Virologic and immunologic studies were performed on 7 infants 1 to 2 years of agewith evidence of intrauterine acquired rubella infection. At that time rubella virus could not be recovered in any of them. Compared to normal control patients, the cutaneous response to vaccination of these patients did not appear impaired, but there was a diminished blast response to vaccinia in their lymphocyte cultures.

The use of combination therapy in leukemia remission

The purpose of this study by Childrens Cancer Study Group A was to explore the effectiveness of combination chemotherapy in the remission maintenance of childhood leukemia. Sixty‐four children with leukemia underwent complete remission with varying doses of prednisone, vincristine, or a combination of 6‐mercaptopurine and methotrexate. They were then treated with 8‐week alternating courses of oral 6‐mercaptopurine and methotrexate. Midway in each course of 6‐mercaptopurine, intravenous actinomycin‐D was given. Similarly, intravenous nitrogen mustard was given during each course of methotrexate. The combination therapy was well‐tolerated. Significantly longer remissions were found in those patients induced with prednisone who received the combination chemotherapy (median = 720 days) when compared with 71 simultaneously treated controls (median = 406 days).

Glycogen content of normal lymphocytes.

Summary and Conclusion Lymphocytes were isolated from the blood of normal individuals. Glycogen content of these cells was determined by the anthrone technic. A significant amount of this polysaccharide was found in these cells suggesting that normal lymphocytes contain more of this substance than the granulocyte. These findings are in contradiction to observations made on these cells by PAS method and assumptions based on chemical glycogen determinations of leukemic lymphocytes.

Hereditary spherocytosis and sickle cell trait in the Negro

Four cases of hereditary spherocytosis associated with sickle cell trait in aNegro family are reported. The salient diagnostic features of spherocytosis with hemoglobin S trait are described and the importance is mentioned of considering this combination as a possibility in the Negro presenting with hemoglobin AS and evidence of hemolytic disease.

EARLY RESPONSE TO INDUCTION THERAPY AND OCCULT TESTICULAR LEUKEMIA (OTL) AT END THERAPY PREDICT LATE RELAPSE (LR) IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

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<0.001. DFS after testicular bx was significantly better in pts without OTL (p.0.005). BM relapse and death rates were significantly higher in pts with OTL than in boys (N=26, 9.9%) who did not undergo bx. In a subsequent trial, CCG 160 series, of 1490 pts with complete data, dl4BM ranked 6th (p<0.001) by univariate analysis and 4th (p<0.001) by multivariate analysis as a predictor of DFS. CCG 160 pts were randomized after 2 yrs of DFS to receive 2 or 3 yrs of maintenance therapy. The dl4BM was the most significant predictor of DFS after late randomization, The observed/expected (O/E) failure rate in pts with dl4 M1 (<5% blasts), M2(5-25%), or M3(>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.