Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study.

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 micromol*h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 micromol*h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P =.007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P =.043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse--the Children's Cancer Group Experience.

BACKGROUND: Childhood acute lymphoblastic leukemia is the single most common childhood malignancy. Despite substantial improvements in therapy, cases in which relapse occurs are still more common than newly diagnosed cases of many other childhood cancers. The survival of patients who relapse despite improved therapy continues to be of interest. METHODS: One thousand one hundred forty-four relapses and 28 second malignant neoplasms were identified among the 3712 eligible patients enrolled on Children's Cancer Group trials between 1983 and 1989. The details of treatment after relapse were not accessible. Subsequent secondary event free survival and overall survival were examined by the site of and time to initial relapse. A variety of potential prognostic factors were examined employing the log rank statistic and Wilcoxon regression model. RESULTS: Rates of 6-year survival (+/- standard error) after isolated bone marrow, isolated central nervous system (CNS), and isolated testis relapse were 20%+/-2%, 48%+/-4%, and 70%+/-5%, respectively. Rates of survival after isolated bone marrow relapse at 0-17 months, 18-35 months, and after 36 months were 6%+/-2%, 11%+/-2%, and 43%+/-4%, respectively. Rates of survival after isolated CNS relapse at 0-17 months, 18-35 months, and after 36 months were 33%+/-4%, 59%+/-5%, and 72%+/-8%, respectively. Rates of survival after isolated testis relapse at 0-17 months, 18-35 months, and after 36 months were 52%+/-11%, 57%+/-10%, and 81%+/-5%, respectively. Rates of survival after combined bone marrow and CNS or testis relapse at 0-17 months, 18-35 months, and after 36 months were 9%+/-5%, 11%+/-6%, and 49%+/-7%, respectively. CONCLUSIONS: Substantial survival at 6 years is evident among several subsets of this unselected group of heterogeneously treated children, namely, those with isolated or combined bone marrow relapse after 36 months and those with isolated extramedullary relapse at any time. Second malignant neoplasms are rare thus far.

Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review.

BACKGROUND: Early response to therapy is defined as the initial response prior to Day 28 of treatment, the conventional time of marrow evaluation. The number of reports linking early response to therapy with the ultimate outcome of childhood acute lymphoblastic leukemia is substantial and growing. When this study began, these experiences had yet to be comprehensively reviewed. METHODS: A comprehensive search of the published literature yielded contributory reports of 14 trials conducted in the United States and Europe. In addition, unpublished data from one Children's Cancer Group trial were made available. Outcome measures were standardized by conversion to ratios of the incidence of adverse events among poorer and better responders. RESULTS: Early response to therapy was an independent prognostic factor in each of the 15 trials, which together included more than 10,000 patients. The incidence of slower early response ranged from 2-33%, with various measures and criteria used in different trials. Patients with a slower early response were 1.5-6.1 times (median, 2.7) more likely to have an adverse event than patients with a more rapid early response, however defined. Early response maintained prognostic significance after the exclusion of induction failure and within risk strata defined by age, white blood cell count, and/or immunophenotype. Its significance was also maintained in multivariate analyses where performed. CONCLUSIONS: Early response to therapy, whether determined by evaluation of bone marrow or peripheral blood, is a consistent, independent prognostic factor in childhood acute lymphoblastic leukemia. Slower early response may serve as a useful surrogate for outcome, a more complex end point, in investigations of the cellular and molecular determinants of resistance to therapy. It may also allow early identification of a patient subpopulation for whom current therapy is less effective and alternative strategies may be justified.

Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Leukemic cells from a significant number of children with acute lymphoblastic leukemia (ALL) express protein antigens characteristic of both lymphoid and myeloid cells, yet the clinical significance of this immunophenotype has remained controversial. In the current study, we have determined relationships between myeloid antigen expression and treatment outcome in a large cohort of children with newly diagnosed ALL. A total of 1,557 children enrolled on risk-adjusted Children's Cancer Group studies were classified as myeloid antigen positive (My+) or myeloid antigen negative (My-) B-lineage ALL (BL) or T-lineage ALL (TL), according to expression of CD7, CD19, CD13, and CD33 antigens on the surface of their leukemic cells. My+ patients in both BL and TL groups were more likely than My- patients to have favorable presenting features. Induction therapy outcome was similar for My+ and My- patients in both the BL and TL categories. Importantly, 4-year event-free survival (EFS) was similar for My+ BL (77.0%, standard deviation [SD] = 4.0%) versus My- BL (75.9%, SD = 1.8%) and for My+ TL (72.7%, SD = 7.1%) versus My- TL (70.1%, SD = 5.7%). An overall relative hazard rate (RHR) of 0.89 (P = .49) was determined by a cross strata analysis for My+ versus My- patients. Moreover, similar EFS and RHR also were found when My+ and My- BL patients were compared according to National Cancer Institute risk classification. Thus, patients with My+ ALL have similar treatment outcomes as My- ALL patients. In contrast to previous studies, this result was independent of treatment risk category, demonstrating that myeloid antigen expression was not an adverse prognostic factor for childhood ALL.

Ultrasonography for thyroid screening after head and neck irradiation in childhood cancer survivors.

We prospectively used ultrasonography to detect thyroid abnormalities in 96 long-term survivors of childhood cancer, who received head and neck radiation therapy at a median age of 8.9 years. The median time interval since irradiation was 10.8 years (range 5.6-22.8 years). Most survivors of leukemia received 24 Gy cranial irradiation for central nervous system prophylaxis; patients with solid tumors received between 20 and 66 Gy (median 37.5 Gy). The total evaluation included clinical history, physical examination, thyroid function tests, and thyroid ultrasonography; radionuclide scans were performed in patients whose abnormalities persisted on subsequent ultrasound exams. Clinical history and physical examination revealed thyroid abnormalities in 14 patients (15%), but ultrasound detected abnormalities in 42 patients (44%). These findings included inhomogeneity (n = 29), cysts (n = 15), and nodules (n = 22) and occurred in nearly half of patients treated with 15 Gy or more directly to the thyroid gland. Radionuclide scans confirmed the presence of thyroid nodules in 13 of 15 patients with ultrasonographic evidence of nodules. Six patients had thyroid neoplasia, including one case of papillary carcinoma. All patients with neoplasia had nodules demonstrated on ultrasonography. Our experience suggests that in childhood cancer survivors, ultrasonography is a sensitive, affordable, and noninvasive means of detecting subtle parenchymal abnormalities. We recommend thyroid ultrasonography for childhood cancer survivors who received head and neck irradiation. A baseline study should be obtained within 1 year of completion of therapy. The frequency of subsequent examinations should be based on the radiation dose and the patient's age at the time of irradiation.

Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: a pediatric oncology group study.

PURPOSE: A phase I trial was conducted in children with refractory solid tumors to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and pharmacodynamics for topotecan administered by a 30-min infusion for 5 consecutive days. PATIENTS AND METHODS: Forty children with a variety of recurrent solid tumors, including nine patients with neuroblastoma and 10 with brain tumors, were given topotecan as a 30-min infusion for 5 consecutive days, beginning with a dose of 1.4 mg/m2/day. The dose was escalated in 20% increments after establishing that DLT was not present at the prior dose. Drug toxicity was graded using standard criteria. Dose-limiting toxicity was defined as grade 3 or 4 nonhematopoietic toxicity or grade 4 hematopoietic toxicity lasting > 7 days. Pharmacokinetic studies were performed during the first infusion course. RESULTS: The DLT was hematopoietic and involved both platelets and neutrophils. Grade 4 hematopoietic toxicity of brief duration was seen at all dose levels. Over half of the patients received red blood cell transfusion support, and 19/40 received platelet transfusions. Hospital admissions for fever and neutropenia or for documented infections occurred in 32 of 169 courses of therapy. Gastrointestinal symptoms with nausea and vomiting or diarrhea were mild to moderate in 12 of the 40 patients. Antitumor responses were seen in three patients with neuroblastoma. An additional four patients (one with neuroblastoma, two with anaplastic astrocytomas, one with Ewing) had stable disease with continued therapy for > 6 months. Using a limited sampling model, pharmacokinetic studies were performed in 36 of the 40 patients. Topotecan lactone and total clearance were similar to those reported in other pediatric populations receiving topotecan by continuous infusion. A pharmacodynamic relation between systemic exposure to topotecan lactone and myclosuppression was observed. CONCLUSIONS: In heavily pretreated children, the MTD for topotecan given by intermittent 30-min infusion for 5 days is 1.4 mg/m2 without GCSF and 2.0 mg/m2/day with GCSF. The dose-limiting toxicity is hematopoietic. Data from this study provide the basis for further studies of topotecan in children with cancer.

The frequency and consequences of varicella exposure and varicella infection in children receiving maintenance therapy for acute lymphoblastic leukemia.

PURPOSE: The frequency and cost of varicella and varicella exposure were determined in children receiving maintenance chemotherapy for acute lymphocytic leukemia, and the cost of a preventative strategy using the varicella vaccine was estimated. PATIENTS AND METHODS: Retrospective analysis of clinic and hospital records for 472 children at 12 sites who were receiving maintenance chemotherapy on Protocol 105 of the Childrens Cancer Group. RESULTS: During a mean maintenance period of 2 1/2 years there were 120 exposures to varicella among susceptible children (10/100 patient-years). During the same period there were 60 cases of varicella (4.6/100 patient-years). Half of the cases of varicella occurred without a known exposure. Exposures and varicella resulted in significant omission or delay in chemotherapy. Total medical charges for varicella-related events were $492,000 ($470 per varicella exposure; $7,450 per case of varicella). A proposed preventative strategy using varicella vaccine after 6 months of maintenance therapy would theoretically reduce varicella-related charges by 80%. CONCLUSIONS: Varicella exposure and varicella are common in this patient population. The use of varicella vaccine during the early maintenance period should be considered to prevent these events. This strategy is likely to be safe, and will save significant medical charges, drug omission, disease-related morbidity, hospitalization, and work and school disruption.

Comparison of treatment regimens for pediatric lymphoblastic non-Hodgkin's lymphoma: a Childrens Cancer Group study.

PURPOSE: Patients with lymphoblastic non-Hodgkin's lymphoma (LB NHL) were randomized to treatment with either modified LSA2L2 or ADCOMP, which added daunorubicin (DAUN) and asparaginase (L-ASP) to the methotrexate (MTX), cyclophosphamide (CYT), vincristine (VCR), and prednisone (PRED) (COMP) regimen, in a clinical trial to determine the relative effectiveness and toxicity of the two regimens. PATIENTS AND METHODS: Patients with LB NHL were eligible for this randomized study if they were less than 22 years of age at diagnosis and had < or = 25% blasts in the bone marrow. Of 307 patients registered, 281 were fully eligible and assessable. Patients were stratified by extent of disease at diagnosis. RESULTS: The 5-year event-free survival (EFS) rate for patients with localized disease was 84%, and for patients with disseminated disease, 67%. There were four relapses in 28 patients with localized disease. Two hundred six patients had mediastinal primary tumors and despite local radiation, 34 of 63 failures in these patients involved the primary tumor site with or without other involvement. After adjusting for extent of disease at diagnosis, the regimens did not differ significantly with respect to risk for adverse events. The acute toxicity was primarily neutropenia and thrombocytopenia, with greater initial toxicity in patients on the LSA2L2 regimen. Three patients developed acute myelogenous leukemia. CONCLUSION: Long-term EFS in children with LB NHL can be achieved in the majority of patients. Disease progression, which includes recurrence at the primary tumor site, is a major cause of treatment failure in patients with mediastinal presentations. Addition of DAUN and L-ASP to the COMP regimen does not produce a more effective treatment than LSA2L2.

Monitoring residual disease in acute lymphoblastic leukemia: therapeutic implications.

The polymerase chain reaction (PCR) has been applied to detect occult leukemia (ALL) cells in patients with acute lymphoblastic leukemia who are otherwise considered in complete remission by traditional morphological examination of bone marrow specimens. The combined data from the clinical studies published to date suggest that a consistent pattern for residual disease disappearance over many months exists for patients who remain in complete remission for an extended period of time. Conversely, a pattern of residual disease persistence and reappearance preceding clinical findings exists for the majority of patients who ultimately relapse. The ability to detect residual ALL disease near the end of chemotherapy or after the completion of treatment in some patients who otherwise are deemed likely to be cured of their malignancy raises the possibility that mechanisms other than leukemia cell cytotoxicity are influencing the outcome for this disease.

Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: a Childrens Cancer Group report.

PURPOSE: This study was designed to evaluate the effect on CNS relapse (CNSR) and overall relapse rates of blast cells in the CSF containing < or = 5 cells/microL at the time of diagnosis of intermediate-risk acute lymphoblastic leukemia (ALL) in children entered onto a large randomized multicenter prospective therapeutic trial (Childrens Cancer Group [CCG]-105). PATIENTS AND METHODS: We studied outcome in terms of CNSR and event-free survival (EFS) in 1,544 patients who successfully completed remission-induction therapy and had been randomized to one of four systemic chemotherapy regimens and to one of two CNS prophylaxis regimens. We compared outcome between 1,450 patients who had varying degrees of pleocytosis but no blasts in the CSF at diagnosis (blast-negative group) with 94 who had blasts detected in the CSF after cytocentrifugation but had a total CSF WBC count of < or = 5/microL (blast-positive group). RESULTS: No statistically significant differences in overall CNSR or EFS rates were observed between the two groups and no differences were found when analyzed according to age or WBC count at diagnosis, sex, or type of CNS prophylaxis (intrathecal [IT] methotrexate [MTX] alone v IT MTX plus 18 Gy cranial irradiation [CXRT]). CONCLUSION: In intermediate-risk ALL, there was no significant difference in CNSR and systemic relapse rates after standard presymptomatic CNS therapy between patients with a CSF WBC count < or = 5/microL and those without identifiable blasts in the CSF. These findings suggest that certain approaches to therapy, such as that used in this study, may eliminate the need for any additional special treatment directed at this subset of patients with CSF blasts.

Blasts in CSF with a normal cell count do not justify alteration of therapy for acute lymphoblastic leukemia in remission: a Childrens Cancer Group study.

PURPOSE: The Childrens Cancer Group (CCG) requires both a CSF WBC count of more than five cells per microliter and demonstration of blast cells in the cytocentrifuge specimen to support a diagnosis of CNS relapse. We reviewed the CSF examinations of patients with intermediate-risk acute lymphoblastic leukemia (ALL) to determine the clinical significance of blast cells reported in the cytocentrifuge when the total CSF cell count was normal. PATIENTS AND METHODS: Children treated on CCG-105 for ALL had CSF examinations every 12 weeks during maintenance therapy. The outcome of children who had a positive CSF cytocentrifuge examination without an elevated CSF WBC count was compared with that of children who did not have any CSF blast cells observed. RESULTS: Sixty-four patients had 81 CSF examinations with blast cells and a normal cell count. By Cox life-table regression analysis, patients with blasts had a different disease-free survival (DFS) distribution, with relapses tending to occur earlier (P = .008). However, the DFS for these patients was 63% +/- 9.6% at 5 years from the time of the abnormal cytocentrifuge result as compared with 69% +/- 1.5% for 1,490 children who did not have blasts in their CSF. This difference is not significant. CONCLUSION: Blast cells were infrequently identified in cytocentrifuge preparations of CSF when the cell count was normal. The majority of patients in whom such an event was observed have not experienced a subsequent relapse as measured by life-table analysis at 5 years. The data do not justify changing or augmenting therapy based on cytocentrifuge results alone.

Young adults 16-21 years of age at diagnosis entered on Childrens Cancer Group acute lymphoblastic leukemia and acute myeloblastic leukemia protocols. Results of treatment.

BACKGROUND: Scant data are available on event-free survival (EFS) for young adults with leukemia who were 16-21 years of age at diagnosis. In acute lymphoblastic leukemia (ALL), it is well recognized that children have a better EFS compared with adults, whereas for acute myelocytic leukemia (AML), EFS results seem to be similar. To determine the appropriate treatment for young adults with leukemia, outcome data are essential. METHODS: Young adults entered on the Childrens Cancer Group (CCG) 100 series ALL protocols and the CCG 213 AML protocol were analyzed for EFS and survival. Prognostic factors for EFS also were determined. RESULTS: The actuarial EFS for 143 young adults with ALL treated on the CCG 100 series ALL protocols was 64 +/- 4% at 4 years and 59 +/- 4% at 6 years. The major adverse prognostic feature was leukocyte counts greater than 50,000/microliters. The actuarial EFS for 79 young adults with AML entered on CCG 213 was 32.2 +/- 5.3% at 2 years and 28.6 +/- 5.3% at 3 years. CONCLUSIONS: Young adults with ALL treated on CCG protocols have a 6-year EFS of approximately 60%. This is similar to the EFS for patients 10-15+ years of age at diagnosis treated on the same protocols and better than EFS results reported from most adult trials. Young adults with AML had a slightly inferior outcome compared with younger children.

Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report.

PURPOSE: This study (Childrens Cancer Group [CCG]-105) was designed in part to determine in a prospective randomized trial whether intrathecal methotrexate (IT MTX) administered during induction, consolidation, and maintenance could provide protection from CNS relapse equivalent to that provided by cranial radiation (CXRT) in children with acute lymphoblastic leukemia (ALL) and intermediate-risk features. PATIENTS AND METHODS: We randomized 1,388 children with intermediate-risk ALL to the two CNS regimens. They received either IT MTX at intervals throughout their course of therapy or CXRT (18 Gy) during consolidation with IT MTX during induction, consolidation, and delayed intensification. Systemic therapy was randomized to one of four treatment regimens derived from a regimen used by CCG in recent studies for this patient population and three more intensive regimens based on the Berlin-Frankfurt-Munster trials. RESULTS: Life-table estimates at 7 years show a 93% and 91% CNS relapse-free survival rate for the CXRT and IT MTX groups, respectively. The corresponding event-free survival (EFS) rates are 68% and 64%. The differences are not significant. Patients who received more intensive systemic therapy had a 94% CNS relapse-free survival rate on either CXRT or IT MTX, while patients who received standard systemic therapy had 90% and 80% rates for CXRT and IT MTX, respectively (P < .0001). Patients less than 10 years of age who received CXRT or IT MTX had 72% and 71% EFS rates if they received more intensive systemic therapy. Patients 10 years or older who received CXRT had an improved EFS (61% v 53%) with a more intensive systemic program. This was primarily due to fewer bone marrow relapses (P = .04). CONCLUSIONS: IT MTX during induction, consolidation, and maintenance provides protection from CNS relapse in patients with intermediate-risk ALL equivalent to that provided by CXRT if more intensive systemic therapy is given. The CNS relapse rate with either CXRT or IT MTX is in part dependent on the associated systemic therapy. For intermediate-risk patients less than 10 years of age, IT MTX with an intensified systemic regimen provided CNS prophylaxis comparable to that provided by CXRT, whereas older patients had fewer systemic relapses if they received CXRT.

Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial.

PURPOSE: The Berlin-Frankfurt-Munster (BFM) 76/79 trial of acute lymphoblastic leukemia (ALL) in children produced impressive disease-free survival (DFS) rates with a protocol that began with 8 weeks of intensive therapy, followed by 8 weeks of maintenance therapy, and then another 6 weeks of intensive treatment. The current study was conducted to determine the relative contributions of each of these periods of intense therapy on the DFS rates of ALL patients with intermediate presenting features. In addition, due to concerns regarding the toxicity of CNS irradiation, we compared cranial irradiation (CXRT) with intrathecal methotrexate (IT MTX) administered during induction and consolidation to IT MTX during all phases of the treatment program. PATIENTS AND METHODS: Between May 1983 and April 1989, more than 1,600 children with ALL and intermediate presenting features, as defined by the Childrens Cancer Group (CCG), were entered into a randomized trial that tested four systemic therapy regimens and two CNS programs. RESULTS: The results with a median follow-up of 57 months show that systemic regimens with a delayed intensification (Delint) phase of therapy had a 5-year event-free survival (EFS) rate of 73% compared with the control regimen EFS rate of 61% (p = .006). For children less than 10 years of age, standard three-drug induction and Delint produced a 77% 5-year EFS. IT MTX during all phases of therapy provided CNS protection comparable to the CXRT regimen in children less than 10 years of age. Children 10 years of age or older appear to have a better EFS rate with intensive induction, Delint, and CXRT. CONCLUSION: Delint improves the EFS rate of children with ALL and intermediate presenting features. Maintenance IT MTX can be safely substituted for CXRT for presymptomatic CNS therapy in children with intermediate-risk characteristics less than 10 years of age.

Long-term survival of children with acute non-lymphoblastic leukemia.

Results of a pilot protocol employing chemoimmunotherapy for treatment of 23 children with acute non-lymphoblastic leukemia consecutively diagnosed between 1975 and 1979 are reported. Twenty-two children achieved remission, ten of whom are surviving 6.5-9.5 years after completion of primary systemic therapy (median 7.8 years). Treatment consisted of intermittent courses of Daunomycin, Cytosine Arabinoside, 6-Thioguanine, VP-16, with or without Decadron, Connaught BCG applied between courses of chemotherapy for the first 8 months of treatment, and cranial irradiation/intrathecal Cytosine Arabinoside in early first remission. Five patients with leukemic cells in spinal fluid at diagnosis had myelomonoblastic or monoblastic subtypes and a median diagnostic white blood cell count (WBC) of 149,000/mm3 compared with a median WBC of 12,000/mm3 for the other 18 patients (P = .007).

Reduced cellular immunity to varicella zoster virus during treatment for acute lymphoblastic leukemia of childhood: in vitro studies of possible mechanisms.

To determine the effect of antileukemic therapy on preexisting immunity to varicella zoster virus, we studied 20 children with acute lymphoblastic leukemia maintained in complete continuous remission for greater than 1 year. Cellular immunity was tested by lymphocyte proliferation in response to varicella antigen. Antiviral antibody was measured using the fluorescent antibody to membrane antigen technique. Reduced lymphocyte proliferation was found in 9 of 16 seropositive patients when compared to an age-related control group. On the other hand, antibody titers in patients receiving chemotherapy remained positive and were essentially unchanged from pretreatment values. Shingles occurred in two of nine children with diminished and none of seven patients with normal cellular immunity, suggesting that proliferative responses to varicella antigen may have predicative value in identifying patients at risk for viral reactivation. Additional studies were done to determine if defective antigen presentation or reduced lymphocyte responder-cell frequency could account for the subnormal proliferative responses. Intact presentation of varicella antigens by patient mononuclear cells to parental, virus-specific T-cell blasts suggested that antigen processing was not defective. However, varicella-specific responder-cell frequencies measured by limiting dilution analysis were found to be depressed in most patients, including some with normal proliferative responses. Our findings indicate that therapy for acute lymphoblastic leukemia in children can be associated with depressed cell-mediated immunity to varicella zoster virus even though patients remain seropositive. Further studies suggest that while monocyte-mediated antigen presentation remains intact, virus-specific lymphocyte numbers decline and probably contribute to decreased cellular immunity to varicella zoster virus in children being treated for leukemia.

Lysis of varicella zoster virus infected cells by lymphocytes from normal humans and immunosuppressed pediatric leukaemic patients.

Varicella zoster virus (VZV) is an important cause of morbidity and mortality in immunosuppressed children but little is known of the cellular mechanisms of VZV immunity. We therefore developed a clinically applicable system to study responses to VZV infected cells. Fresh blood mononuclear cells (MNC) from VZV immune donors killed VZV infected fibroblasts in an 18 h 51Cr release assay. The specificity for virus was confirmed by cold target inhibition. An enhancing role for HLA matching was demonstrated using targets mismatched for HLA, and blocking by antibodies to HLA framework and T cell subsets. Cytotoxicity was not blocked with anti-Ia or anti-VZV antibodies. Killing of VZV infected target cells was reduced in seven out of nine VZV antibody positive patients in remission who were receiving maintenance treatment for acute lymphocytic leukaemia. Three of these patients had normal lymphocyte proliferative responses to VZV. Of the two patients with normal cytotoxic responses to VZV, one had reduced proliferation. It therefore appears that presence of VZV antibody, T cell proliferative responses, and cytotoxicity are independently variable. Cytotoxicity may be more susceptible to immunosuppression than either antibody or T cell proliferation.

Intermittent combination chemotherapy with or without bacillus Calmette-Guérin for treatment of acute lymphoblastic leukemia of childhood.

Seventy-four children ranging in age from 6 months to 17.5 years with acute lymphoblastic leukemia newly diagnosed between 1976 and 1979 were entered on a study incorporating intermittent chemotherapy with or without the addition of bacillus Calmette-Guérin (BCG). The chemotherapy program consisted of induction with vincristine, dexamethasone, and intrathecal methotrexate, intensification with adriamycin and asparaginase, central nervous system treatment with cranial irradiation and intrathecal methotrexate, and continuation treatment with 5-day courses of combination chemotherapy administered every three weeks. The first phase of continuation therapy incorporated vincristine, adriamycin, 6-mercaptopurine, and dexamethasone. In the second phase, oral methotrexate was substituted for the adriamycin in non-T-cell patients; in T-cell patients, cytosine arabinoside or cyclophosphamide and methotrexate in alternating cycles were substituted for the adriamycin and asparaginase was added. Total duration of therapy was approximately 2.5 years. Connaught BCG was administered by Heaf gun on days 8 and 15 of each 3-week cycle for the first 8 months of treatment in approximately one-third of the patients. Actuarial disease-free survival with a median follow-up of 59 months shows no difference in outcome between the BCG and non-BCG poor-risk patients. However, there is an improvement in disease-free survival of BCG-treated good- and average-risk girls (P = 0.04). While patients were actively receiving BCG there was also a trend toward the development of fewer significant infections than when patients were not receiving BCG (P = 0.85). Toxicities from BCG administration included satellite rashes, local tenderness, lymphadenopathy, secondary infection, and residual scars. Overall disease-free survival by actuarial analysis is 60% at 6 years; for patients with unfavorable prognostic features it is 40%. In this trial the addition of BCG prolonged the disease-free survival of girls with good- and average-risk prognostic features and also may have decreased the susceptibility to infection while it was being administered. However, the benefit does not appear sufficient to warrant its routine use, especially in view of the toxicities encountered.