Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia.

CONTEXT: Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. OBJECTIVES: To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. DESIGN, SETTING, AND PATIENTS: Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. MAIN OUTCOME MEASURES: Minimal residual disease at the end of induction therapy, measured by flow cytometry. RESULTS: There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. CONCLUSION: Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.

Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was ⩾1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.

Identification of a leukemia-associated antigen of human acute lymphocytic leukemia.

A human leukemia-associated antigen (LAA) has been identified by immunofluorescence and electrophoretic analyses. LAA was detected on the surfaces of cells from patients with acute lymphocytic leukemia (ALL) as well as on the surfaces of leukemia cells from the established cell lines NALM-1, NALM-16, MOLT-4, CCRF-CEM, and RPMI 8402. The antigen was not detected on BALM-1 or Raji cells (established B-cell lines), bone marrow cells from ALL patients in remission, or on blood lymphocytes from normal donors. This antigen was most frequently associated with common ALL (cALL); however, cells from 2 of 12 patients with T-cell ALL and 1 patient with B-cell ALL also expressed this antigen. Under reduced conditions, the antigen had an approximate molecular mass of 100,000 daltons as determined by sodium dodecyl sulfate--polyacrylamide gel electrophoresis and autoradiographic analysis and appeared to be the same cALL antigen that has recently been described by others. The probability that LAA is a normal differentiation antigen was discussed.

Unexpected acute neurologic toxicity in the treatment of children with acute lymphoblastic leukemia.

BACKGROUND: Our current protocol for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to assess the efficacy of methotrexate (MTX) plus L-asparaginase and of etopisode (VP-16) plus cytarabine (ARA-C) during intensive consolidation and continuation therapies and to determine the feasibility of intensifying MTX therapy by the use of divided oral doses of MTX. The protocol was associated with unexpected acute neurotoxicity. There are few reports of such toxic effects during therapy for ALL. PURPOSE: This report describes these toxic effects and outlines our successful approach to the problem. METHODS: The standard four-drug induction regimen consisted of vincristine, L-asparaginase, daunorubicin, and prednisone. In consolidation therapy, oral MTX was given in divided doses (dMTX) of 25 mg/m2 every 6 hours four times daily in four weekly courses concomitant with weekly triple intrathecal therapy--MTX, ARA-C, and hydrocortisone--plus one dose of leucovorin 24 hours after triple intrathecal therapy. Consolidation treatment ended with three daily doses of intravenous VP-16 and ARA-C. The first 16 months of continuation therapy included 6-week cycles of dMTX and L-asparaginase, both given every other week for 5 weeks, with 6-mercaptopurine nightly, and then two doses of VP-16 plus ARA-C and one dose of triple intrathecal therapy. RESULTS: Twenty-five of the 138 patients evaluated had acute neurotoxicity. Ten of the first 72 experienced a seizure or episode of transient neurological deficit 9-11 days following the administration of intravenous ARA-C, VP-16, and triple intrathecal therapy. Despite discontinuation of intrathecal ARA-C, which eliminated simultaneous intravenous and intrathecal treatment with ARA-C, acute neurotoxicity was observed in six previously unaffected patients and six of 42 patients treated after the elimination of intrathecal ARA-C. Therefore, as a second amendment, oral leucovorin was given 24 and 36 hours after dMTX and intrathecal MTX in continuation therapy. No acute neurotoxicity has been seen in 24 patients subsequently entered in the study. CONCLUSION: These findings suggest that folate replacement due to administration of leucovorin modulated MTX toxicity and/or modified an interaction among VP-16, ARA-C, intrathecal therapy, and the central nervous system.

A clinical perspective on cell markers in acute lymphocytic leukemia.

Two hundred consecutive new patients, with acute lymphocytic leukemia (ALL) have been studied with a battery of five cell marker assays to determine if a classification system with prognostic significance can be developed; 182 have been classified among four groups as follows: 33 T-cell, 3 B-cell, 126 common, and 20 undifferentiated ALLs. Patients with T-cell disease are likely to have unfavorable clinical prognostic features and a poor response to therapy. Rare patients with B-cell disease are closely related clinically to non-Hodgkin's lymphoma. Those with common ALL infrequently have unfavorable clinical features and have a superior outcome to that of T-cell patients. Children with undifferentiated markers seem to respond less well to treatment than do those with common ALL, yet may not be identifiable as poor risk by clinical features. What remains to be resolved with further observation is whether these marker patterns are more reliable indicators of prognosis than the usual clinical determinants predisposing to treatment failure (high white blood cell count, mediastinal mass, and central nervous system disease). At the present time, it appears that in the absence of poor-risk clinical prognostic features, patients with common ALL are more likely to have lasting remissions than those with erythrocyte-rosette-positive T-cell disease or those with ALL that is undifferentiated by markers.

Common region of ALL-1 gene disrupted in epipodophyllotoxin-related secondary acute myeloid leukemia.

Translocations at chromosomal band 11q23 characterize most de novo acute lymphoblastic leukemias (ALL) of infants, acute myeloid leukemias (AML) of infants and young children, and secondary AMLs following epipodophyllotoxin exposure. The chromosomal breakpoints at 11q23 have been cloned from isolated cases of de novo ALL and AML. Using an 859-base pair BamHI fragment of human ALL-1 complementary DNA that recognizes the genomic breakpoint region for de novo ALL and AML, we investigated two cases of secondary AML that followed etoposide-treated primary B-lineage ALL. In the first case, the translocation occurred between chromosomes 9 and 11 and the breakpoint at 11q23 localized to the same 9-kilobase region of the ALL-1 gene that is disrupted in most of the de novo leukemias. In the second case the translocation was between chromosomes 11 and 19. The breakpoint occurred outside of the ALL-1 breakpoint cluster region.

Clinical utility of initial terminal deoxynucleotidyl transferase determinations in childhood acute leukemias.

Terminal deoxynucleotidyl transferase (TDT) activity was measured in bone marrow lymphoblasts obtained at diagnosis from 168 consecutive patients with childhood acute leukemia. Absolute concentrations of TDT were increased (greater than or equal to 20 units/10(8) blasts) in samples from 98 of 112 assessable patients with acute lymphocyte leukemia (ALL). The values ranged from less than 1 to 1502 units/10(8) blasts with a median of 90 units contrasted with less than 1 to 219 units (median, 2.6 units) in studies of children without leukemia. Results of an immunofluorescence assay were in good agreement with enzymatic detection of the polymerase. Among 115 patients with adequate marrow smears, 105 had TDT-positive blasts. By contrast, in most children with acute myelogenous leukemia, TDT activity was either undetectable or less than 10 units/10(8) blasts. Although the highest levels of TDT were found in blasts with the common ALL phenotype, quantitative determinations were not significantly related to the major immunological subtypes of ALL or to morphological features or periodic acid-Schiff reactivity of the lymphoblasts. The probability that a newly diagnosed case of leukemia would be ALL was 90% if TDT levels were greater than 20 units/10(8) blasts. We conclude that absolute concentrations of TDT, as determined in this study, are of little value in identifying subclasses of ALL. The immunofluorescence assay, which is much less expensive and easier to perform than the enzyme assay, should prove useful for confirming the diagnosis of ALL and for detecting extramedullary sites of leukemic infiltration.

Failure of late intensification therapy to improve a poor result in childhood lymphoblastic leukemia.

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.

Isolated testicular relapse in acute lymphocytic leukemia of childhood: categories and influence on survival.

Isolated testicular relapse complicating first hematologic remission was identified in 31 of 521 boys with acute lymphocytic leukemia (ALL). Three categories of involvement were apparent and could be related to presenting clinical features, duration of initial complete remission, and length of hematologic remission. Among 12 patients with early testicular relapse, most had unfavorable prognostic features when ALL was first diagnosed. All but two of these children experienced marrow recurrence within seven months of testicular relapse. In contrast, the 12 patients who developed testicular disease late in their clinical course have responded much better to further therapy; ten remain in bone-marrow remission for a median of four years beyond testicular relapse. Similarly, five of the seven patients with subclinical testicular leukemia, found at elective biopsy, continue in marrow remission for prolonged periods. Early testicular recurrence is a sign of drug-resistant disease; late recurrence after elective cessation of therapy may represent residual, incompletely treated but still responsive leukemia.

Etoposide (VP-16) with prednisone and vincristine for the treatment of refractory 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.

Serum aminotransferase elevation during and following treatment of childhood acute lymphoblastic leukemia.

PURPOSE: The clinical significance of methotrexate (MTX)-induced hepatic toxicity in children with acute lymphoblastic leukemia (ALL) is poorly defined. Therefore, we conducted a study to determine whether intensive MTX therapy could be safely delivered despite isolated serum ALT elevations in children with ALL. PATIENTS AND METHODS: A total of 243 children with B-precursor ALL were treated with extended pulses of oral divided-dose MTX (dMTX). Serum ALT levels were measured approximately every 7 weeks during therapy, as well as after its cessation. By protocol design, treatment was continued without modification in the presence of ALT elevations if there was no other evidence of liver dysfunction. RESULTS: Of 239 assessable patients, 159 (66.5%) had an ALT level > or = 180 IU/L during therapy and 28 patients (17.6%) had one or more values > or = 720 IU/L. After the completion of therapy, only 17 of 104 assessable patients have had one or more elevated ALT value. Eight of these 17 patients (47%) are hepatitis C virus (HCV)-seropositive. The remaining nine children had subsequent normal or near normal ALT values, and none have clinical evidence of liver disease. CONCLUSION: Our data show that MTX can be safely delivered without dose modification in patients with isolated ALT elevations and that continued therapy does not lead to clinically apparent liver disease. ALT elevations are not a reliable predictor of the presence or extent of hepatic injury, and persistently increased ALT values following the completion of ALL therapy are rare in the absence of HCV infection. Continued MTX therapy allows for increased dose-intensity and may improve outcome in children with ALL.

Continuous infusion high-dose cytosine arabinoside in refractory childhood leukemia.

Ten pediatric patients with refractory leukemia received continuous infusion high-dose cytosine arabinoside (ara-C) according to one of two escalating dosage schedules: (1) a 500-mg/m2 rapid infusion loading dose followed by 3.5 g/m2 per day continuous infusion daily for four consecutive days, or (2) a 600-mg/m2 rapid infusion loading dose followed by 5.0 g/m2 per day continuous infusion daily for four consecutive days. Major toxicity at the lower dosage level was grade IV hematopoietic aplasia of three weeks' duration. At the higher dosage level, there was a prohibitive toxicity in multiple organ systems including transient noncardiogenic pulmonary edema, fungal infections, peritonitis, severe diarrhea, transaminase elevations, and one treatment-related death due to acute renal failure. In contrast to other methods of administration of high-dose ara-C, no CNS toxicity occurred. Oncolytic responses were seen in all patients and two achieved brief, partial remissions. Steady-state plasma ara-C concentrations were 13 to 40 mumol/L at the 3.5-g/m2 dosage level and 10 to 225 mumol/L at the 5-g/m2 dosage level; CSF concentrations at both dosages ranged from 2 to 5 mumol/L. Intracellular levels and ratios of 1-beta-D-arabinofuranosylcytidine-5' triphosphate and endogenous deoxycytidine 5' triphosphate in marrow blasts varied widely at steady state during infusion. No positive correlation existed between steady-state plasma ara-C levels, toxicity, oncolytic effect, or intracellular nucleotide concentration.

Phase I trial of continuous infusion carboplatin and etoposide in children with refractory acute leukemia: a Pediatric Oncology Group study.

PURPOSE: The purpose of this phase I study was to determine the toxicities and response to continuous infusion carboplatin in combination with a fixed dose of etoposide (VP-16) in children with refractory acute leukemia. PATIENTS AND METHODS: From January 1989 to February 1992, 20 patients received 28 courses of treatment. Each course of treatment consisted of a 1-hour intravenous (IV) infusion of VP-16 100 mg/m2/d for 5 days, followed by a 23-hour IV infusion of carboplatin each day. The initial, total 5-day dose of carboplatin (1,000 mg/m2) was escalated by 250- to 375-mg increments to a final, total dose of 1,875 mg/m2 over 5 days. RESULTS: Significant marrow suppression was observed in all patients, with prolonged marrow aplasia at the 1,875-mg/m2 dose level. Grade III diarrhea occurred in three patients; 10 patients experienced life-threatening infection and three had severe thrombocytopenic bleeding. Major marrow responses (two complete remissions and two partial remissions) occurred in four patients (20%). CONCLUSION: In view of the apparent antileukemic efficacy and minimal extramedullary toxicity, carboplatin deserves further study in a phase II trial.

Results of treatment of advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and cytarabine.

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.

Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide.

PURPOSE: To describe the occurrence of secondary acute myeloid leukemia (AML) in children with acute lymphoblastic leukemia (ALL) treated with etoposide (VP-16). PATIENTS AND METHODS: Two hundred five consecutive children with early B-lineage ALL were treated according to the Dallas/Fort Worth (DFW) protocol between January 1986 and July 1, 1991. Therapy included a four-drug induction followed by consolidation and continuation phases of nightly oral mercaptopurine (6-MP) and repetitive courses of divided-dose oral methotrexate (dMTX) and asparaginase (L-asp). Three doses of VP-16 and cytarabine (Ara-C) were given during consolidation and later, during continuation, two doses were given 3 to 4 days apart, every 9 weeks. Intrathecal (IT) chemotherapy was given throughout the treatment period. RESULTS: Two hundred three of the 205 patients entered remission. Only eight of these 203 children have had a bone marrow relapse (ALL). However, 10 other children have developed secondary AML 23 to 68 months following the diagnosis of ALL. Overall event-free survival (EFS) at 4 years is 79.3% +/- 5.1%, with a risk of secondary AML at 4 years of 5.9% +/- 3.2%. CONCLUSION: This experience provides strong evidence for a link between epipodophyllotoxin therapy and secondary AML since none of these children received alkylating agent therapy or irradiation. This serious complication raises concern as to the appropriate use of epipodophyllotoxins in the treatment of childhood ALL.

Intensive oral methotrexate protects against lymphoid marrow relapse in childhood B-precursor acute lymphoblastic leukemia.

PURPOSE: To describe the use of combination chemotherapy, including divided-dose oral methotrexate (dMTX), for children with B-precursor acute lymphoblastic leukemia (ALL). dMTX produced prolonged MTX exposure on an outpatient basis. PATIENTS AND METHODS: Two hundred forty-three patients were treated from January 1986 to May 1992. dMTX was given weekly during consolidation and biweekly for the first 16 months of continuation therapy with mercaptopurine (6-MP) and asparaginase (L-ASP). Initially, etoposide (VP-16) and cytarabine (Ara-C) pulses were included. Treatment continued for 30 months with single-dose weekly MTX replacing dMTX during continuation, part 2. Unexpected acute neurotoxicity was eliminated by the addition of leucovorin. VP-16 and Ara-C were omitted in the face of acute myelogenous leukemia (AML). RESULTS: Two hundred thirty-nine patients entered remission: 16 had a lymphoid marrow relapse, two each with testicular or CNS relapse; 19 a CNS relapse; 16 secondary AML; three other second malignancies; two withdrew for transplant; three died in remission; 16 withdrew because of noncompliance, and nine withdrew with toxicity. Event-free survival (EFS) at 4 years was 73 +/- 4%; 81 +/- 4% for 150 patients with better risk features and 60 +/- 7% for 93 with high-risk features. Lymphoid marrow relapse-free survival in the standard- and high-risk patients was 94 +/- 3% and 86% +/- 6%, respectively. The most common adverse event was secondary AML in the standard-risk group and isolated CNS relapse in the high-risk group. CONCLUSION: This therapy produced an overall EFS similar to other published regimens, but the pattern of failures is very different, with few patients having a lymphoid marrow relapse. These data suggest that highly effective therapy for children with ALL can be delivered on an outpatient basis using a regimen featuring repetitive dMTX.

Sequential changes in platelet function and coagulation in leukemic children treated with L-asparaginase, prednisone, and vincristine.

Coagulation and platelet function in 13 children with acute lymphoblastic leukemia were studied sequentially during a remission induction with L-asparaginase, prednisone, and vincristine. In the first weeks of therapy, which included four doses of L-asparaginase coagulation was characterized by significant decreases in plasma concentrations of plasminogen, antithrombin III alpha 2-macroglobulin, and fibrinogen. All measures gradually returned to normal after complication of L-asparaginase therapy. In the latter part of induction treatment, clotting times, especially partial Thromboplastin time, decreased significantly, while levels of factors V and VIII increased with recovery of platelet counts. At this time, 6 patients had an increased in vitro platelet aggregation response to adenosine diphosphate, and their partial thromboplastin times were significantly shorter than those of patients without increased aggregation. Concurrent abnormalities in coagulation and platelet function may account for the thrombotic complications that develop in some children receiving induction therapy with these agents.

Second central nervous system prophylaxis in children with acute lymphoblastic leukemia who relapse after elective cessation of therapy.

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.

Serial cranial computed-tomography scans in children with leukemia given two different forms of central nervous system therapy.

Cranial computed tomography (CT) was used to estimate the frequency and permanence of brain abnormalities in 108 consecutive children with acute lymphoblastic leukemia (ALL). Fifty-five patients received cranial irradiation (1,800 rad) with intrathecal methotrexate (RT group) and 53 patients received intravenous and intrathecal methotrexate without irradiation (IVIT group). Continuation treatment included sequential drug pairs for the RT group and periodic IVIT methotrexate for the other group. After 12 to 24 months of serial evaluation, five (9%) of the 55 patients in the RT group have had CT scan abnormalities, compared to 10 (19%) of 52 in the IVIT group (p = 0.171). Fourteen of the 15 patients with CT scan abnormalities had focal or diffuse white-matter hypodensity; these have reverted to normal in most cases, reflecting a dynamic process. While such CT findings are of concern and may be an early indicator of central nervous system toxicity, this remains to be proven. Therapy should not be altered on the basis of abnormal CT scans alone but in the context of the entire clinical situation.

Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a pediatric oncology group study.

PURPOSE: In an effort to improve outcome for children with advanced B-cell malignancies, a treatment plan based on a published regimen that consists of four courses of fractionated cyclophosphamide (cyclo) given with doxorubicin (doxo) and vincristine (VCR) was intensified by alternating with sequential high-dose methotrexate (MTX) and cytarabine (Ara-C), given in conjunction with intrathecal (IT) MTX and Ara-C. PATIENTS AND METHODS: From October 1986 to October 1992, 133 eligible patients were enrolled: 74 with B-cell (surface immunoglobulin-positive [Slg+] acute lymphoblastic leukemia (B-ALL) and 59 with stage IV small noncleaved-cell lymphoma (SNCCL). The median age was 8 years; there were 103 males and 30 females. Abdominal tumor masses were prominent in 63 cases (33 B-ALL and 30 stage IV SNCCL). RESULTS: Complete remission (CR) was achieved in 66 B-ALL and 57 stage IV patients (93% overall). At 4 years, the estimated event-free survival (EFS) rate is 65% +/- 8% for patients with B-ALL and 79% +/- 9% for those with stage IV SNCCL. Among patients with CNS involvement, 23 of 36 remain in CR (4-year EFS rate, 64% +/- 13%). Relapses occurred early; only 3 patients relapsed after completion of therapy. Thirteen relapses occurred in the marrow, three in the CNS, and six in other sites. Of 11 CNS-positive patients who relapsed, only two recurred primarily in the CNS. CONCLUSION: The results of this study indicate that with intensified chemotherapy an increasing potential for cure exists for patients with B-ALL and stage IV SNCCL.