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Increasing numbers of childhood ALL survivors have increased the need to assess the physical and psychosocial functioning of this group in a careful manner. This article reviews data on the frequency and types of second malignancies, structural and functional changes in the central nervous system, endocrine effects on growth and reproduction, and psychosocial aspects of development. Most long-term survivors of ALL do not have serious or life-threatening medical problems; however, medical and psychosocial problems may not be insignificant and may require coordinated management over prolonged periods.

High-dose methotrexate (HDMTX) added to a basic regimen of chemotherapy proved superior to cranial irradiation and sequentially administered drug pairs (RTSC) in prolonging complete remissions in children with "standard-risk" acute lymphocytic leukemia. To extend this result to more contemporary risk groups, we reclassified the patients according to methods of the Pediatric Oncology Group (POG), the Childrens Cancer Study Group (CCG), the Rome workshop, and St Jude Total Therapy Study XI. By life table analysis, 70% to 78% of patients with a favorable prognosis would remain in continuous complete remission (CCR) at 4 years if treated with HDMTX. Uniformly lower CCR rates could be expected with RTSC, especially in St Jude better-risk patients. HDMTX also would show greater efficacy than RTSC in the CCG average-risk and POG poor-risk groups, but the results appear inferior to those being achieved with intensified regimens for high-risk leukemia. Although both therapies would provide adequate CNS prophylaxis in favorable-risk groups, RTSC would offer greater protection in patients classified as being in a worse-risk group by St Jude criteria. We conclude that HDMTX-based therapy, as described in this report, would be most effective in patients with a presenting leukocyte count of less than 25 x 10(9)/L, of the white race, aged 2 to 10 years, and having leukemic cell hyperdiploidy without translocations.

Using flow cytometric techniques, we determined the pretreatment distribution of DNA content in propidium iodide-stained leukemic blasts from 205 children with "standard-risk" acute lymphoblastic leukemia (ALL). Risk assignment was based on an initial WBC count less than 100 X 10(9)/L, no thymic mass, no meningeal leukemia, and lymphoblasts lacking sheep erythrocyte receptors or surface immunoglobulin. A single aneuploid leukemic line was detected in 74 cases (36.1%): 70 hyperdiploid and four hypodiploid. For hyperdiploid cases, the DNA index (DI, or ratio of the DNA content of leukemic v normal G0/G1 cells) ranged from 1.06 to 2.0 (median, 1.20). A secondary leukemic line with hyperdiploid cellular DNA content was identified in 21 cases with diploid primary lines. Children whose primary leukemic line showed a DI greater than or equal to 1.16 (n = 57) had significantly better responses to treatment than did those with either a diploid DI (n = 130; P = .002) or values in the range of 1.01 to 1.15 (n = 14; P = .001). The relative risk of failure for hyperdiploid cases with DI greater than or equal to 1.16, corresponding to greater than or equal to 53 chromosomes, was one-third that of the other two groups. Treatment responses of patients with both diploid and hyperdiploid lines were identical to those associated with single diploid lines, but significantly worse than those associated with single hyperdiploid lines with DI greater than or equal to 1.16 (P = .016). The most favorable prognostic variables selected by a Cox proportional hazards model were: DI greater than or equal to 1.16 (P = .001), white race (P = .022), WBC less than or equal to 25 X 10(9)/L (P = .032), age between 2 and 9 years (P = .075), and hemoglobin less than 7.0 g/dL (P = .094). DNA index greater than or equal to 1.16 retained its significant prognostic impact even after adjustment for other variables (P = .001). With the combination of DI greater than or equal to 1.16 and WBC less than or equal to 25 X 10(9)/L, one can identify a group of children with ALL who have a low probability of relapse when treated with current therapy. If they remain disease-free after longer follow-up, it may be advisable to treat them with less intensive, hence less toxic, chemotherapy than patients with higher WBC counts or lower DI values.

Analyses of bone marrow blast cells collected at diagnosis and relapse from 68 children with acute lymphoblastic leukemia (ALL) demonstrated changes in the expression of cell markers in one-fourth of the patients. Loss of the common ALL antigen (CALLA) was a frequent change, occurring in 8 of the 51 cases initially classified as common or pre-B ALL. The HLA-DR antigen was either acquired or lost in 5 of the 68 cases, terminal deoxynucleotidyl transferase was lost in 6 of 25 cases, and reactivity of the T10 antigen with monoclonal antibodies was increased in 6 of 17 cases of non-T cell ALL. Conversion to acute nonlymphoblastic leukemia, so-called lineage switch, was noted in two cases of common ALL and one of pre-B ALL, coinciding with the loss of CALLA. Results of chromosomal analyses in cases with a loss of CALLA implicated several mechanisms in the observed phenotypic changes. In six cases, including each instance of lineage switch, the original karyotype had been replaced by an entirely different abnormal karyotype, suggesting clonal selection or induction of a second malignancy. In another case, the evidence suggested clonal evolution. Our findings demonstrate that sequential phenotypic and cytogenetic studies may yield valuable insights into the mechanisms of leukemic recurrence and may have implications for treatment selection.

Glucocorticoid receptor (GR) levels were quantitated in leukemic blasts from bone marrow aspirates of 249 children with acute lymphoblastic leukemia (ALL) who were entered on two St. Jude Total Therapy Studies. Of these, 235 were evaluable for analysis of the relation of GR levels to clinical outcome. For the 42 patients in the earlier Total Therapy Study IX, lower GR levels (less than 16,000 sites/cell) were associated with both induction failure and more frequent relapse (p less than 0.01) [Cancer Research, Vol. 42, p. 4801 (1982)]. When patients with 'high-risk' features (leukocyte count greater than 100 X 10(3)/mm3, positive erythrocyte rosette test, central nervous system involvement, and mediastinal mass) were excluded, lower receptor levels were still associated with early and more frequent relapse (p less than 0.02). The other 193 evaluable patients were consecutively admitted to Total Therapy Study X, in which patients with 'standard-risk' or 'high-risk' features were assigned to separate protocols--XS and XH, respectively. Induction chemotherapy in both protocols consisted of prednisone, vincristine and L-asparaginase; patients in the XH protocol received additional epipodophyllotoxin (VM-26) and cytosine arabinoside twice a week for 2 weeks preceding the conventional induction therapy. To compare the prognostic value of GR level in Study X with that of Study IX (which included both 'high-risk' and 'standard-risk' patients but did not separate them into different protocol groups), children in the XH and XS protocols were analysed together. The proportion of patients with 'standard-risk' features was the same in the two studies: 69% in Study IX and 73% in Study X. In Study X, which had a significantly better treatment result (p less than 0.001), lower receptor levels were not associated with induction failure, but were correlated with more frequent relapse (p less than 0.05). When patients in XH and XS protocols were analysed separately, however, receptor levels were no longer related to treatment outcome. Thus, GR level in childhood ALL has prognostic value, but it is not an independent factor and its importance is related to the efficacy of treatment.

Cyclic combination chemotherapy was administered to 26 patients with acute lymphoblastic leukemia who had relapsed in the bone marrow greater than or equal to 6 months after elective cessation of therapy. Each patient had been in initial continuous complete remission for 36-111 months (median, 47 months). Prednisone, vincristine, and doxorubicin induced second complete remissions in all patients within 1 month. Continuation therapy consisted of alternating 6-week courses of 6-mercaptopurine/methotrexate and vincristine/cyclophosphamide with intervening reinforcement courses of prednisone/doxorubicin, for a total of 18 months. All patients received 4 weeks of late intensification therapy with the same agents used for remission reinduction. Periodic intrathecal methotrexate was given as reprophylaxis for subclinical central nervous system leukemia. The estimated rate of continuous failure-free survival at 5 years is 31% +/- 17% (2 SE). Eight patients remain free of leukemia for 42 + to 65+ months after completing therapy a second time. Adverse second events included 11 hematologic, 1 testicular, and 3 meningeal relapses. Patients who relapsed at more than 12 months after the completion of initial treatment have had significantly longer second remissions than patients whose first remissions were shorter (p = .04). None of the other six factors we analyzed showed predictive strength. These end results indicate that intensive cyclic continuation chemotherapy, as described here, will secure durable second remissions in approximately one-third of the children with late bone marrow relapses.

Serum lactic dehydrogenase (LDH) levels were measured at diagnosis in 293 children with "standard-risk" acute lymphoblastic leukemia (ALL) to determine the prognostic value of this biologic feature. Standard risk assignment was based on an initial leukocyte count of less than 100 X 10(9)/L, the absence of a mediastinal mass, the absence of meningeal involvement, and the presence of lymphoblasts lacking sheep erythrocyte receptors or surface immunoglobulin. Serum LDH levels ranged from 97 to 6,595 U/L, with a mean of 547 U/L. Higher LDH levels were associated with higher leukocyte counts, lower blast cell DNA indices, lower platelet counts, a larger spleen size, and nonwhite race. LDH levels were not related to the percentage of marrow S-phase cells, liver size, French-American-British (FAB) classification, hemoglobin levels, age, sex, or the presence of the common ALL antigen on marrow blasts. Patients with the highest LDH levels (greater than 1,000 U/L) were most likely to fail treatment, whereas those with the lowest levels (less than 300 U/L) had the lowest risk of failure (P less than .0001). The prognostic significance of serum LDH level was retained in a subset of patients that included only those with leukocyte counts less than 25 X 10(9)/L (P = .0018). When 11 presenting characteristics were subjected to multivariate analysis, serum LDH level was found to have independent prognostic strength, contributing clinically important information to that gained from leukocyte count. Early measurement of serum LDH could be useful in identifying a group of standard-risk ALL patients with a high relapse hazard.

As the intensity of cancer chemotherapy has been reported to influence clinical response for several drug-sensitive cancers, we have investigated the relation between systemic exposure to high-dose methotrexate (HDMTX) and clinical response in childhood acute lymphocytic leukemia (ALL). A total of 108 consecutive, previously untreated children with "standard-intermediate risk" ALL were randomized to receive postinduction therapy with HDMTX (1000 mg/m2 iv over 24 hours weekly for 3 weeks, then every 6 weeks for 72 weeks), superimposed on conventional therapy with low-dose 6-mercaptopurine (6MP; 50 mg/m2 orally per day) and methotrexate (MTX; 25 mg/m2 orally per week). The systemic clearance of HDMTX ranged from 40 to 131 ml/minute/m2 among these patients, yielding MTX steady-state plasma concentrations (Cpss) ranging from 9.3 to 25.4 microM during the infusion. The group of patients (n = 59) with median MTX Cpss less than 16 microM during the HDMTX infusion had a higher probability of having any relapse than patients (n = 49) with MTX Cpss greater than 16 microM (P less than 0.05). In a previously reported univariate analysis, patients with MTX Cpss less than or equal to 16 microM were 3.2 times more likely to relapse on therapy (P = 0.01) and 6.9 times more likely to have a hematologic relapse on therapy (P = 0.001). Multivariate and stepwise Cox's regression analyses indicated that MTX Cpss retains its prognostic importance even when other prognostic variables (i.e., DNA Index, WBC, hemoglobin) are considered.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical value of early detection of testicular leukaemia was assessed by elective wedge biopsy during the 12th or 18th month of therapy in children with acute lymphoblastic leukaemia. Biopsy samples were taken in 106 of 238 consecutively treated boys who attained complete remission; only 1 had occult disease. Samples were also taken in 2 boys with testicular leukaemia at diagnosis as soon as they achieved complete remission, and in 14 others at the end of therapy; none showed evidence of leukaemic infiltration. 13 boys, including the 1 with biopsy-confirmed occult disease, had a testicular relapse; 6 of these patients had had negative biopsy findings 12-28 months before relapse. These results indicate that elective testicular biopsy during therapy for childhood leukaemia is of no benefit clinically. They also suggest that routine use of end-of-therapy testicular biopsy should be re-evaluated, since frequency of testicular relapse is low, therapy is effective, and negative biopsy findings do not preclude eventual relapse.

Childhood acute lymphoblastic leukemia with an initial leukocyte count greater than or equal to 100 X 10(9)/L responds poorly to conventional chemotherapy. To extend event-free survival (EFS) in this disease, we devised a protocol that specifies intensive 2-week courses of teniposide (VM-26, 165 mg/m2) plus cytarabine (ara-C, 300 mg/m2), before and immediately after standard 4-week remission induction therapy with prednisone, vincristine, and L-asparaginase. The VM-26 and ara-C combination was also administered intermittently for the first year of continuation treatment with oral 6-mercaptopurine and methotrexate. CNS prophylaxis consisted of periodic intrathecal (IT) injections of methotrexate and delayed cranial irradiation. At a median follow-up of 4 years, the estimated EFS rate for 57 consecutive patients with leukocyte counts of 100 to 1,000 X 10(9)/L was 44%, compared with 10% for matched controls (P less than .001). Remission induction rates in the two groups were similar (82% v 72%, P = .16). Twenty-five patients in the VM-26/ara-C group have survived without adverse events for 2.7 to 6.8 years, whereas only nine of the controls achieved more than a year of EFS. The most common complications during early treatment were acute hyperkalemia from rapid tumor cell lysis and infections due to prolonged marrow aplasia. Continuation chemotherapy was well tolerated. We conclude that VM-26 plus ara-C, added to each phase of an otherwise basic regimen of chemotherapy, will substantially improve prognosis in this high-risk form of childhood leukemia.

Previous studies have found that CNS prophylaxis of children with leukemia, especially young children receiving cranial irradiation, causes neuropsychologic deficits. In the present study, 40 children in continuous complete remission from acute lymphocytic leukemia (ALL) were given a battery of tests to assess memory functioning 5 years after CNS prophylaxis. All children were free of CNS disease at diagnosis and had been randomly assigned to receive CNS prophylaxis with either 1,800 cGy cranial irradiation (CRT) plus intrathecal (IT) methotrexate (MTX) or IT MTX plus intravenous (IV) high-dose MTX (HDMTX). No treatment- or age-related differences were seen on 16 standardized memory measures. However, scores of the combined sample were significantly lower than age-corrected norms on a test of visual-spatial memory and on four scales of verbal memory. Differences in methods or intensity of CNS prophylaxis and study group selection criteria are proposed to explain our findings and to resolve discrepancies with previous reports. The long-term neuropsychological sequelae in these survivors of ALL may be attributable to some common factor, such as the disease itself or systemic and IT chemotherapy.

A treatment plan to achieve better disease control in patients with acute lymphoblastic leukemia (ALL) who relapse after elective cessation of therapy was assessed. The principal modifications were (1) a second preventive treatment of the central nervous system (CNS) at relapse and every six weeks throughout therapy, using intrathecal methotrexate with cytosine arabinoside, and (2) a four-week course of systemic chemotherapy given immediately before therapy was stopped a second time. Twenty-four patients were studied. There have been no meningeal relapses, in contrast to seven among 16 similar patients who were retreated without CNS prophylaxis. Although the median length of second hematologic remission was not significantly different from the outcome in the comparison group, a much higher proportion of patients (eight of 24 versus zero of 17) remain in prolonged reinduced complete remission (48-79 months). Children whose first relapse occurred later than six months after cessation of therapy had significantly longer subsequent remissions. These end results establish the value of intrathecal CNS prophylaxis in relapsed ALL and suggest that a late intensive phase of therapy will extend remissions in a substantial proportion of patients.

In early 1984, we treated 13 consecutive patients with acute lymphoblastic leukemia (ALL) using an induction regimen of rapidly rotated combinations of prednisone, vincristine, asparaginase, teniposide (VM-26), cytosine arabinoside, and high-dose methotrexate (MTX) followed by leucovorin rescue. The intent of this clinical trial, designated Total Therapy Study XI, is to test the hypothesis that greater initial leukemia cell kill will decrease opportunities for the development of drug-resistant mutants, with resultant improvement in the length of disease-free survival. Five patients experienced life-threatening gastrointestinal toxicity within three weeks of the start of treatment. One died. Three other patients had severe abdominal pain, abdominal distention, diarrhea, and weight loss, but not gastrointestinal bleeding. In the remaining five patients, toxicity was rapidly reversible, and each child was able to complete the planned course of chemotherapy. The study was then amended to switch high-dose MTX from the induction phase to the consolidation phase, allowing at least one week for mucosal recovery. Among the next 28 patients who were treated, none showed evidence of severe gastrointestinal toxicity. Patients now receive high-dose MTX alone as consolidation therapy and are tolerating it adequately. Drug timing should be examined critically when intensified multiple-agent regimens are being devised for initial treatment of ALL.

We devised a plan of intensive chemotherapy to address the problem of inadequate results of treatment in children with acute lymphoblastic leukemia in first bone marrow relapse. Immediately after remission was induced with four conventional drugs, a two-week intensification course of teniposide and cytarabine was given to eradicate subclinical leukemia. Patients in remission were then treated for two years with rapid rotation of pairs of drugs that were not cross-resistant and periodic courses of the same agents used to induce remission. A second complete remission was induced in 31 of the 39 patients in whom response to chemotherapy could be assessed. The probability of maintaining bone marrow remission in these patients for one year was 0.38 +/- 0.19 (95 percent confidence interval); the two-year probability was 0.29 +/- 0.17. Seven patients completed the treatment program, five of whom have been in continuous second complete remission 17 to 20 months after the cessation of therapy. Children whose initial bone marrow remission lasted less than 18 months had significantly poorer responses to retreatment than did those with a longer first remission (P = 0.004). Intensive chemotherapy, as described here, may save half of the children with acute lymphoblastic leukemia in whom bone marrow relapse occurs after a relatively long initial remission.

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B-derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.

This clinical study, begun in 1975, tested the efficacy of early and delayed intensification treatments in children with acute lymphoblastic leukemia. Regardless of presenting features, all patients received 4 weeks of conventional induction therapy with daily prednisone and weekly vincristine and daunorubicin. One-third were randomized to receive, in addition, two doses of asparaginase during induction therapy, while another one-third received four doses of both asparaginase and cytarabine after remission induction. Preventive central nervous system therapy uniformly included 2400 rads cranial irradiation and five doses of intrathecal methotrexate. Remissions were maintained with daily p.o. mercaptopurine and weekly i.v. methotrexate. Of the 277 assessable patients, 254 (92%) entered complete remission, and 102 (37%) remain clinically free of leukemia for 4.6 to 8.0 years (median, 6.3 years). The three treatment groups showed no significant differences in either remission induction rate or outcome, even when the analysis was based on risk assignment. A "late intensification" phase of therapy, added to the maintenance protocol for 65 patients who had been in continuous complete remission for 14 to 30 months, failed to extend remission durations, as judged from statistical comparison with matched controls (p = 0.84). When tested as a time-dependent covariate in the Cox proportional-hazards model, delayed intensification again showed no important effect on duration of complete remission. We conclude that limited early or aggressive late intensification of therapy, as described here, does not improve outcome in childhood acute lymphoblastic leukemia.

Fifty children with acute lymphoblastic leukemia (ALL) in first to fifth relapse were treated with a three-drug reinduction regimen consisting of prednisone (40 mg/m2/d for seven days), vincristine (1.5 mg/m2 on day 1) and etoposide (VP-16, 250 mg/m2 on days 1 through 3). The intent was to assess the efficacy of VP-16 in an otherwise conventional reinduction plan, especially in patients who had previously received teniposide (VM-26), the close congener of VP-16. Among the 46 patients who received at least two courses of the therapy, 16 (0.34) achieved complete remission. Seven others showed improvement in their bone marrow status. Each child had been heavily pretreated with prednisone and vincristine, and 14 had received VM-26. That seven patients judged to be clinically resistant to VM-26 had complete responses to prednisone-vincristine-VP-16 indicates that prior treatment with one podophyllotoxin derivative does not preclude responses to the other. We are uncertain about the pharmacologic basis of these results but suggest that the increased dosage and more frequent administration of VP-16, relative to that of VM-26, was sufficient to overcome apparent resistance to the latter compound. Remission durations ranged from one to eight months (median, four months), emphasizing the need to devise more effective continuation therapy, including investigational agents such as the epipodophyllotoxins.

To address the problem of historically poor results in the treatment of children with advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia (ALL), an intensive chemotherapy regimen was devised using the most effective single agents in high-dose short courses. Treatment commenced with a fractionated schedule of intravenous (IV) cyclophosphamide (300 mg/m2 every 12 hours for six doses) followed immediately by Adriamycin (50 mg/m2) and vincristine (1.5 mg/m2) with combined intrathecal (IT) methotrexate and cytarabine. Predictably, this treatment produced virtually complete disappearance of all tumor and profound myelosuppression. Immediately on hematologic recovery, IV high-dose methotrexate (1,000 mg/m2 over 24 hours) followed by IV cytarabine (400 mg/m2 over the next 48 hours) was administered with leucovorin rescue and repeated IT treatments. The treatment sequence described above is repeated four times, with the dose of cytarabine doubled in succeeding courses, up to 3,200 mg/m2. The entire planned therapy required approximately 24 weeks. Since 1981, we treated a total of 29 children with this approach, 19 of whom had massive unresectable intraabdominal tumor. According to initial extent of disease, 17 were classified as stage III, four as stage IV non-Hodgkin's lymphoma (NHL), and eight as B cell ALL. Eight of the 12 patients with stage IV NHL or B cell ALL had initial involvement of the CNS. Twenty-seven of 29 patients (93%) attained a complete remission. Fourteen of 17 stage III NHL patients remain disease free, for periods ranging from 3+ months to 4 1/2+ years. The actuarial estimate of the proportion of stage III patients remaining disease free at 2 years is 81%. Results in patients with initial involvement of the CNS and/or marrow are much less favorable, with only two of ten patients who attained remission apparently being cured. In addition to stage, the initial serum lactic dehydrogenase (LDH) level emerged as a prognostic indicator, higher levels (over 1,000 IU/L) being associated with the worst prognosis (P less than .05). Major toxicity consisted of severe hematopoietic suppression and febrile episodes associated with neutropenia. We conclude that this treatment is highly effective for advanced-stage Burkitt's tumors in children free of initial CNS involvement.

Alpha-2 interferon, produced in Escherichia coli using recombinant DNA techniques, was administered to 17 children with refractory acute lymphoblastic leukemia (ALL) in relapse, two children with TdT-positive, Philadelphia chromosome-positive chronic myelocytic leukemia (CML) in blast crisis, and one child with B cell (SIg+) non-Hodgkin's lymphoma (NHL) in a second extramedullary relapse. An initial 2-week intravenous (IV) phase of interferon was followed by a 3-month subcutaneous (SC) maintenance phase if patients had an objective response or disease stabilization without significant bleeding or infectious complications. When interferon dosages were escalated from 3 to 100 X 10(6) U/m2 in the first phase of therapy, there was rapid progression of disease in the first four patients treated, prompting a modification of the treatment plan. The last 16 patients enrolled received fixed dosages of interferon (ie, 10, 20, 30, and 50 X 10(6) U/m2 administered to four subjects each). One child with T cell ALL had an 11-month complete remission; the patient with lymphoma had a dramatic but brief response; three others (one CML and two ALL) showed disease stabilization for 3 to 6 months with a definite oncolytic effect in two of the three patients. The remaining 15 patients had progressive disease within 2 months and were removed from the study. Acute toxicity included a flu-like syndrome in all patients, increased serum transaminase levels in five, seizures in three (two cases temporally related to fever and one to a thrombocytopenic subarachnoid hemorrhage), and prolonged activated partial thromboplastin times in seven. This phase I-II trial of recombinant alpha-2 interferon demonstrated definite activity without dose-limiting toxicity.

We determined the intellectual and academic status of 40 children with acute lymphoblastic leukemia who had experienced a primary isolated relapse in the CNS by analyzing the results of psychoeducational tests administered a median of 6.1 years after the relapse. Mean scores for full-scale IQ (87.5), verbal IQ (86.7), performance IQ (90.3), as well as academic achievement in reading (89.8), spelling (83.9), and mathematics (83.5) were significantly below normal expectations for age. Twenty percent of the group were mentally retarded and were receiving special educational assistance. The best clinical predictors of full-scale IQ were the number of radiation therapy courses, age, and the presence or absence of cerebral pathology as measured by computed tomography (CT). Children who were younger at the time of treatment, who received two courses of radiation therapy, and who had clinical seizures and structural abnormalities of the brain as detected by CT had the poorest psychological outcome. Although the psychoeducational consequences of CNS relapse and its attendant treatment are significant, these must be balanced by consideration of the relatively low probability of long-term survival without aggressive therapy. Recognition of this type of delayed morbidity with systematic surveillance and prompt attempts at rehabilitation may decrease or at least minimize these sequelae.

Improvements in therapy for childhood acute lymphoblastic leukemia (ALL) have led us to reevaluate the prognostic significance of lymphoblast characteristics at diagnosis. From application of univariate and multivariate statistical methods, we determined the relationship of five blast cell features to treatment outcome in 250 patients who were enrolled in two clinical trials at this center from May 1979 through April 1982. Karyotype ploidy, lymphoblast morphology, and immunophenotype were each significantly related to prognosis as measured by time to failure, while periodic acid-Schiff reactivity and glucocorticoid receptor number lacked prognostic implication for this patient population. In addition, clinical features of initial WBC count, age, and race were also significant independent variables in predicting treatment response. By multivariate analysis, both ploidy and morphology contributed prognostic information to a clinical model based on WBC count, age, and race. If the model was adjusted for impact of ploidy, however, French-American-British morphology no longer contributed additional prognostic information. Our findings suggest that many traditional biological features used to estimate prognosis in ALL can be discarded in favor of clinical features (leukocyte count, age, and race) and cytogenetics (ploidy) for planning of future clinical trials.