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Dose and dose intensity are believed critical for attaining a maximal therapeutic effect in drug-responsive tumor systems. Childhood acute lymphoblastic leukemia may be an example of such a drug-responsive system as it is cured with current chemotherapy in a majority of cases. Between August 1981 and May 1983, the Childrens Cancer Study Group enrolled 209 children with ALL and unfavorable presenting features in CCG-193P, a trial based on the Berlin Frankfurt Munster 76/79 regimen. The cumulative delivered dose of each medication was recorded prospectively. Patients who completed the intensive portion of therapy in continuous complete remission were ranked by the percentage of protocol required drug delivered from the initiation of therapy to that date. No association was found between delivery of any single drug and subsequent disease-free survival. However, when patients were ranked by the sum of the percentages of protocol vincristine, l-asparaginase, and anthracycline delivered, children in the approximate middle and lower tertiles were 3 and 5 times more likely to have had a subsequent relapse than were those in the upper tertile (P = 0.025, test for trend). Delivery of the full protocol prescribed dose of these agents may have been critical, but corroboration is certainly needed. Only prospective trials can determine if children with acute lymphoblastic leukemia and unfavorable presenting features might benefit from greater use of vincristine, l-asparaginase, and/or anthracycline.

One hundred fifty-three children with ALL were diagnosed in Norway in the period August 1975-December 1980. One hundred thirty-two of them received 3 infusions of methotrexate as consolidation therapy combined with methotrexate intrathecally as CNS prophylaxis. Eleven (44%) of the total 25 methotrexate cases with WBC above 50 X 10(9)/L were in CCR after 4 1/2-10 years. Two more cases had discontinued therapy, while in second remission. The event-free survival of all diagnosed 32 children in Norway with WBC above 50 X 10(9)/L was 37%. Seven infants below the age of 1 year are included in the 32 cases.

Five weekly doses of triple intrathecal (IT) chemotherapy (methotrexate, hydrocortisone, cytosine arabinoside) starting on day 1 of treatment were added to systemic induction therapy in a regimen (Arm 3) that was compared to three other regimens (Arms 1, 2, and 4) in which central nervous system (CNS) prophylaxis was initiated after complete marrow remission (CR) was attained. The CR rate for Arm 3 was only 83% as compared to 91-92% for other Arms. The lower CR rate was the result of a significantly higher death rate during induction for patients receiving early CNS prophylaxis (10.6 vs 0.9-3.5%). These differences were only observed in high risk patients as defined in the study. The early death rate was especially high (30%) in Arm 3 for children who were less than 2 years of age. Infection was the primary cause of morbidity and mortality. Severe infection following the initiation of induction therapy was found in 16.7% of patients on Arm 3 vs 1.8-6% on other regimens. Immediate triple IT chemoprophylaxis during induction therapy of acute lymphoblastic leukemia as used in this study appears to be associated with increased susceptibility to infection and this form of CNS prophylaxis has increased hazards of morbidity and mortality in infants and other high risk patients.

Cytogenetic studies were performed in 331 patients with ALL diagnosed at the National Institutes of Health between January 1961 and January 1976. Four patients had constitutionally abnormal genotypes, three had Down's syndrome, and one had a D/G translocation. Aneuploidy was observed in the pretreatment bone marrow in 49/115 (42.6%) of this series exhibited several general characteristics: aneuploid cells usually coexist with normal stem cells, hyperdiploidy is predominant and wide ranging aneuploidy clusters around a major cell line. The most common chromosomal group involved in aneuploidy is the G group (p=0.001) and the next most common is the B group (p=0.01). Aneuploidy disappeared after successful achievement of remission, and new clones developed in 12 patients during relapse. Two of the four patients originally thought to have a Ph1 chromosome, on trypsin Giemsa handing were proved to have a 21q- chromosome. A higher incidence of aneuploidy was noted in patients under one year or more than 20 years of age and was also higher in patients with low or elevated WBCs at diagnosis. The appearance of aneuploid cells in the bone marrow at the onset or later in the disease is of no prognostic significance but persistence of these lines and the development of total aneuploidy signals a poor prognosis. Eradication of aneuploid cells is therefore essential for the achievement of a long remission and progress to a permanent cure.

Although the prognosis of children with ALL has improved markedly, approximately one-half of children continue to relapse. Clinical and biologic features of ALL have been studied at the time of diagnosis and many of these features have been shown to predict the risk of relapse, permitting tailoring of therapy based on relapse hazard. Results of studies of the Pediatric Oncology Group (POG) detailed here demonstrate that high white blood cell (WBC) count at diagnosis, very young or older age within childhood, and the presence of a mediastinal mass or central nervous system leukemia predict a poor prognosis within the context of certain therapies. However, not only age and WBC count, but immunophenotype of ALL as well, were especially predictive of prognosis in these POG studies. The information reviewed here has special importance for the planning of clinical trials for children with ALL.

To assess the racial differences in survival of children with acute lymphocytic leukemia, we analyzed data for 1,675 white and 126 black children, diagnosed from 1955 to 1969. Blacks had a significantly shorter median survival and lower one-year and three-year survival rates than whites. There was substantial variation in racial differences by age. In addition, much of the variation between races seemed to be due to socioeconimic factors rather than strictly racial ones. Identification of the specific factors responsible for the poorer survival of children from lower social classes is sorely needed.

Children with ALL who have a high probability of excellent response, long-term survival, and cure when treated with widely available standard therapy can be identified at the time of diagnosis. Others can be identified who are at high risk of failure to respond, early relapse, and death. The importance of such prognostic characteristics is so great that they should be considered in the selection of appropriate treatment for each patient. Prognostic factors also must be considered in the design and analysis of clinical trials. All prognostic factors are not equally significant and many of them are closely associated. It is possible to rank them in importance and usefulness by appropriate statistical methods. As additional prognostic factors are identified, and as more effective and more specific therapies are developed, the relative importance of prognostic factors will change.

The predictable prognostic factors were analysed among 174 children with acute lymphoblastic leukemia who were treated during the last ten years under different protocols in one institute. It was confirmed that the children under 1 year of age, or with T-cell marker, had poor prognosis. The initial WBC of more than 50,000/mm3 was less significant as a predictable risk factor with chemotherapy of the newer protocols. Cell kinetic study was found to be of no more help than the initial WBC, but a more accurate prediction could be obtained by measuring glucocorticoid receptor of leukemic cells. The prognosis was poor among children with initial WBC of more than 50,000/mm3 and receptors of less than 20,000 sites per cell.

We studied the karyotype in 81 consecutively diagnosed children with acute lymphocytic leukemia (ALL) treated at one institution on a randomized treatment protocol. In 75 patients (93%), a morphological cytogenetic result was obtained, and 57 (65%) were successfully G-banded. Of the 75 patients, 46 (61%) showed abnormal chromosomes, mainly hyperdiploidy and pseudodiploidy, and 29 had no detectable abnormality. Our findings confirmed that the karyotype has prognostic significance. Duration of complete remission was 93% at 42 months for patients with high hyperdiploidy (greater than 50). For patients with an apparently normal karyotype, it was 58%; and for patients with structural abnormalities it was 15%. The significance of these findings was confirmed by multivariate analysis, which showed age and karyotype to be the most important determinants of duration of remission.

One hundred eighty-seven patients diagnosed with acute lymphoblastic leukemia (ALL) between 1972 and 1975 were evaluated for height 6.4-8.8 years (median 7.2 years) from the time of diagnosis of their disease. All patients had been treated on protocols CCG-101/143 conducted by the Childrens Cancer Study Group. After induction of remission, patients received either cranial radiation plus six doses of intrathecal methotrexate, craniospinal radiation, or craniospinal radiation plus abdominal radiation, followed by systemic maintenance chemotherapy for either 3 or 5 years. No significant difference was observed in the distribution of height percentiles at the time of diagnosis compared to expected population standards. After treatment an excess (P less than 0.001) was observed in the proportion of patients in the lower percentiles in conjunction with a decrease in the proportion of patients in the higher percentiles. After adjustment for height at diagnosis, the only factor found to have significant impact on attained height percentile was exposure to craniospinal plus abdominal radiation (P less than 0.001) where there was a fivefold excess in the proportion of patients below the fifth percentile for height. Craniospinal radiation only was not associated with a greater reduction in attained height percentile when compared to cranial radiation only.

Eighteen (72%) of 25 evaluable and previously untreated patients with adult acute lymphoblastic leukemia entered complete remission (CR) following induction therapy with adriamycin, vincristine, and prednisone in a Southwest Oncology Group study. Remission maintenance therapy with methotrexate and 6-mercaptopurine resulted in a median duration of CR of 10.2 months. The addition of Adriamycin to prednisone and vincristine may be beneficial in slow responders or nonresponders to these two drugs and in patients with initially high peripheral blood blast counts.

Bone marrows of 41 untreated children and adolescents with acute lymphocytic leukemia were studied by combined immunologic and histochemical methods at the time of diagnosis. Eleven were classified as T-cell lymphoblastic leukemias (27%) on the basis of cytochemical stains and E-rosette assay. The patients in this group has low median age of 8 years, relatively low median WBC of 13.4 x 10(3)/cc, 6/11 were female, and only 2/5 males had a mediastinal mass. The girls had a lower median age than boys (7 vs 9 years), none had mediastinal masses or extramedullary involvement, and their survival was greater than 27 months compared to 14 months for the boys (P less than 0.01). All patients were enrolled and treated on the (then) currently active CCSG protocols for ALL. This study emphasizes the fact that not all patients with T-cell ALL have poor prognosis, that sex could be an important factor affecting survival, and that the difference in survival could not be adequately explained by differences in the initial WBC.

Prognostic factor evaluation is a frequent and desirable investigative activity in clinical trials. Nevertheless, a number of errors in the evaluation of such factors occur quite commonly. Many of these problems are due to inappropriate statistical interpretation of the analyses that are conducted. A detailed discussion of several problem areas is given. In the area of childhood ALL trials, issues related to the appropriate choice of disease end-points for analysis of prognostic factors are discussed.

The biologic impact and clinical toxicity of Corynebacterium parvum administered at a dose of 5 mg/M2 by intravenous or subcutaneous routes were evaluated in 18 children receiving combination chemotherapy for maintenance of acute lymphoblastic leukemia (ALL) in remission. Several nonspecific immunologic and hematologic parameters were evaluated. Patients were also monitored for changes in cutaneous sensitivity to histamine. No changes in any parameter were observed in patients after only one course of C parvum injection. However, after 6-10 courses, glass-adherent peripheral blood leukocytes of C parvum-treated patients augmented the response of PHA-stimulated autologous lymphocytes. In all nine patients studied who received C parvum injection subcutaneously for at least six months, there were significant increases in the mean bone marrow myelocyte-erythrocyte (ME) volumes compared to pretreatment values. These results suggest that periodic evaluations are desirable in patients receiving repeated administration of C parvum, since changes in immunologic and hematologic responses may be demonstrable only after several injections. In contrast to the reported experience in adults, subcutaneous C parvum administration children was not well tolerated, whereas intravenous infusion was generally well tolerated.

The results of cessation of therapy (COT) in 64 long-term survivors (disease-free survival of five years or more) of acute lymphoblastic leukemia (ALL) were analyzed to determine the incidence of relapse off therapy. Thirty-seven of the patients had intermittent central nervous system (CNS) prophylaxis. Total follow-up from diagnosis varied from 5.75 to 27.75 years. The median time off therapy was three years (range, 8 months to 26 years). Eighty-six percent (55/64) of the patients continue in their initial remission. Eight patients had relapse, and one patient had a morphologically different leukemia at recurrence. All the relapses occurred between five to eight years from diagnosis and the cumulative rate of relapse for the period was 0.14. There was no significant difference in the rate of relapse for those receiving CNS prophylaxis (0.08) versus those not receiving CNS prophylaxis (0.19). The difference in the relapse rates for boys (0.24) versus girls (0.04) was statistically significant (P = 0.04). Isolated testicular relapse (ITR) was not seen in any of the 34 boys. The present study confirms the earlier observations by others that relapse is uncommon in ALL patients remaining in remission longer than seven to eight years. ALL patients treated with intermittent CNS prophylaxis administered throughout the period of maintenance chemotherapy appear to be at no greater risk for relapse off therapy than those treated with high-dose initial cranial irradiation and intrathecal methotrexate. The longer duration of therapy and the use of a repetitive reinduction regimen for maintenance seem to be associated with a decreased risk of ITR after discontinuation of therapy for boys and men. There appears to be a small but definite risk of "second" leukemia in the long-term survivors of leukemia.

The morphological classification of ALL based on the FAB co-operative group's criteria is capable of identifying 10-15% of children with L2 disease who, given similar treatment, will fare less well than the 85-90% with the L1 variant. The significant features defining L2 morphology are a low cellular nuclear: cytoplasmic ratio and the presence of nucleoli. Children with L2 disease do not have higher leucocyte counts but are older, have "common" ALL less frequently, and more often have well-preserved marrow function at diagnosis. Their poor outlook is manifest not only by their higher relapse rate but also by a higher proportion failing to remit in the first instance. L2 morphology does not necessarily "breed true" and can arise in a small proportion of patients with previous L1 disease at the time of relapse. Other striking morphological features of lymphoblasts, including azurophil granules, vacuoles and "hand mirror" cells, have yet to have their significance defined, though the latter feature may be an unfavourable finding.

Patients with acute lymphoblastic leukemia who have a mediastinal mass at the time of diagnosis are said to have a poor prognosis. However, many factors which may not be independent contribute to the success of treatment. We compared the disease characteristics and results of therapy in children having large mediastinal masses and lymphoblastic leukemia without mediastinal mass. Patients with a mediastinal mass had less evidence of marrow failure but were burdened with considerably more leukemic cells as measured by peripheral blood white count and extent of lymphadenopathy. Since the presence of mediastinal mass was strongly associated with these and other poor prognostic characteristics, we used multivariate techniques to determine which characteristics were independently associated with an increased risk for relapse. White count, extent of lymphadenopathy, age, and sex were significant predictors of early relapse, but when controlled for these variables the presence of a mass did not predict prognosis.

In this retrospective multicentric study, we report on early deaths (ie, those that occurred during the first month of treatment) in a total of 943 newly diagnosed ALL pediatric patients registered from 1976 to 1981 at 21 centers of the AIL- AIEOP . Objectives of this study were as follows: (1) to verify the incidence and the cause of early death in a wide population of children with ALL and (2) to elucidate factors associated with early death and therefore to identify "high-risk" groups of patients. Out of the 943 ALL patients, 39 (4.1%) early deaths were registered. Main causes were infection, 20 patients (51.3%); hemorrhage, 11 patients (28.3%); uric acid nephropathy, 2 patients (5.1%); cardiac failure, 3 patients (7.6%); syndrome of inappropriate antidiuretic hormone secretion, 1 patient. Two patients died during the first week of unknown cause. Thirteen factors measured at diagnosis and possibly influencing the early death rate were analyzed. Using the chi-square test, only three of these factors (age, mediastinum status, surface markers) appear to have any significant influence on the early death rate. We also tried to determine how therapy influences this process by analyzing variations in the early death rate, other factors being equal. Significant differences in the early death rates were encountered in AIEOP protocols using different induction regimens.

Children with acute lymphocytic leukemia (ALL) who have a "lymphoma syndrome" (LySLk) defined by the presence of at least three of the following criteria: a) Hg greater than 10 g/dl, b( lymph nodes greater than 3 cm, c) spleen below umbilicus, d) liver below umbilicus, and e) mediastinal mass, appear to represent a subgroup of ALL. These children have a poor prognosis for survival when treated with standard chemotherapy for ALL. We performed a retrospective review of 21 patients at Children's Memorial Hospital with LySLk diagnosed from Jan 24, 1977 to July 8, 1981 and of the surface markers on their leukemic cells at diagnosis. Surface markers identified included E-rosettes (E), surface immunoglobulin (Slg), and common ALL antigen (cALLA). Four patients were cALLA positive and E-rosette negative; nine patients were E-negative, cALLA negative; six patients were E positive, cALLA negative. In two patients E-rosettes could not be accurately determined because of a low percentage of lymphoblasts in the samples studied. Follow-up data on cALLA-positive and cALLA-negative patients revealed 4/4 cALLA-positive patients with no evidence of disease (NED) at 22 + to 45 + months from diagnosis and 2/16 cALLA-negative patients NED at 19 + and 57 + months. Thus it appears that the majority of children with LySLk have lymphoblasts which are cALLA negative. Patients who meet clinical criteria for LySLk but whose surface markers are E negative, cALLA positive may have a better prognosis and may represent a separate subgroup of patients with ALL and, therefore, should be given therapy appropriate for their prognostic classification by more standard criteria, such as white blood count, age, and sex.

Fifty-six untreated patients with childhood with acute lymphoblastic leukemia (ALL) were randomized to receive one of three remission induction regimens: vincristine and prednisone (VP), vincristine, prednisone and daunorubicin (VPD), or vincristine, prednisone and adriamycin (VPA). The complete remission rate was similar for all three groups. Although the anthracycline regimens caused somewhat more rapid leukemic cell reduction than the VP only group, this difference was not significant. Labeling index reduction between study days 1 and 5 was significantly greater (p less than 0.001) with an anthracycline than for the VP group, but there was no difference between the two anthracyclines. Granulocytopenia during induction was significantly increased (p less than 0.05) in both the VPD and VPA groups as compared with VP alone. A significantly higher rate of infectious morbidity (p less than 0.01) was associated with the addition of either anthracycline, but to date no significant differences in remission duration or survival have been observed. The addition of anthracyclines to VP for remission induction in childhood ALL has theoretical advantages, but may be undesirable because of increased morbidity.

Four groups of children with poor-prognosis disease were selected for study from the Medical Research Council childhood ALL trials. Each group was reviewed for distinguishing clinical features and response to therapy. The four comprised those with a diagnostic white cell count over 50 X 10(9)/l, those with a mediastinal mass, those less than a year old at diagnosis, and those presenting with meningeal involvement. They accounted for 17, 5.3, 2.6, and 3%, respectively, of unselected children with ALL. As expected, all four categories showed significantly inferior relapse-free survival to the rest, but only in patients with a mediastinal mass and in the under-1-year-olds did a recognisable syndrome emerge clearly associated with other clinical features. These two syndromes, high-count T-ALL and high-count infant null-ALL, are logical candidates for alternative therapy. Established meningeal disease also continues to present a major therapeutic challenge.

This paper reports late effects and health status of 198 children who had cancer or leukemia diagnosed under 2 years of age and their therapies electively withdrawn. This series (92 neuroblastoma [NBL], 57 Wilms' tumor [WT], 46 acute lymphoblastic leukemia [ALL], and 3 non-Hodgkin's lymphoma) was followed for 1-12 years after discontinuation of therapy. Thirty-three children were diagnosed before 1973, 92 between 1973 and 1977, and 73 after 1977 in 16 Italian Pediatric Oncology Centers. As of December 1983, 176 children were reported to be alive and without evidence of primary cancer by physicians responsible for their care. One child died from a second primary tumor, two from late recurrences of the primary cancer, and three from other causes; eight were alive with evidence of primary cancer; and eight were lost to follow-up. Kyphoscoliosis was found in 22 children and other musculoskeletal anomalies in 8. Neurological sequelae were observed in 8 out 35 children with ALL treated with radiotherapy (RT) and intrathecal methotrexate. All but one were in continuous complete remission when they developed seizures (three cases), leukoencephalopathy (three cases), or intracerebral calcifications (two cases). One child had cardiomyopathy and subsequently died from cardiac failure: he had received doxorubicin (400 mg/m2) and mediastinal RT (13 Gy) for NBL. Growth impairments were observed in children with NBL and WT.

Age at initial diagnosis in ALL has been identified in numerous studies to be an important prognostic factor. Data were examined from a large series of patients entered on ALL clinical trials of the Childrens Cancer Study Group during the period 1972-1983. These data confirm the importance of age as a prognostic factor and show that even after adjustment for other factors by multivariate analysis, age remains a highly significant predictor of outcome. The data suggest that there are three main age groups with different prognoses: infants (less than 1 year at diagnosis), the 1-9 age group, and those 10 or greater. The best prognosis is found in the intermediate age range and the worst in the infant group. While age is presumably a surrogate factor reflecting the effect of factors with more direct and explainable relationships to the disease process, analysis of data in this review and from other recent studies do not yet adequately explain the age effect in terms of other prognostic factors.

Early intensive therapy might be critical in improving failure-free survival for children with acute lymphoblastic leukemia. Between 1973 and 1977, 107 children received vincristine and prednisone (VP) induction and 30 received the same two agents plus an anthracycline (VPA). Ninety-nine of the VP-treated group and all 30 of the VPA-treated patients achieved complete remission. At a median observation time of 10 years, 59 of 137 children remain in continuous complete remission. Failure-free survival was 37% for the VP group and 63% for the VPA group (p = 0.02). Failure-free survival for boys who received VP was 28%, compared with 68% for boys who received VPA (p = 0.007). All 11 extramedullary relapses and all seven relapses occurring beyond 3.8 years from diagnosis (three testicular and four bone marrow) were observed among the VP group. We conclude that use of an anthracycline during remission induction therapy influenced failure-free survival and that early results of successful antileukemic therapy in children must be confirmed by follow-up progress reports.