Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.

Urolithiasis in pediatric patients with acute lymphoblastic leukemia.

We evaluated the incidence, timing, and consequences of urolithiasis in children with acute lymphoblastic leukemia (ALL). A total of 20 patients with urolithiasis were identified from 2095 patients with ALL treated at St Jude Children's Research Hospital on consecutive protocols between 1968 and 1998. For remission induction therapy, all patients received daily prednisone; continuation chemotherapy regimens differed by protocol with some including pulses of prednisone or dexamethasone and others no glucocorticoid. Patients with urolithiasis were older at diagnosis of ALL than those without urolithiasis (median age, 7.5 vs 5.0 years; P=0.03) and less likely to be black (P=0.03) than white or Hispanic, but sex and treatment era did not differ. Presenting symptoms included abdominal or flank pain, hematuria, and dysuria. All stones analyzed biochemically were calcium stones. The incidence of urolithiasis after completion of therapy was 1.8 per 10 000 person-years. Compared to this baseline rate, the relative risk of urolithiasis was 45 (P<0.01) during induction therapy, 22 (P<0.01) during continuation therapy with glucocorticoids, and 5.1 (P>0.05) during continuation therapy without glucocorticoids. Urolithiasis occurred 4.5 times more often during continuation treatment with glucocorticoids than without (P<0.05). Seven patients (35%) had recurrent urolithiasis. Patients with ALL are at risk of developing calcium renal stones during chemotherapy, especially when a glucocorticoid is included.

Energy expenditure in children undergoing hematopoietic stem cell transplantation.

Prior studies suggest that patients undergoing hematopoietic stem cell transplantation (HSCT) for malignancy have nutritional needs that are greater than their estimated needs. To determine whether energy estimation equations accurately predict energy expenditure of pediatric patients undergoing HSCT, we prospectively compared the estimated energy expenditure (EEE) and measured energy expenditure (MEE) of 40 patients at four time-points. We also investigated whether energy requirements changed during the transplant period. MEE was determined by indirect calorimetry. Data from 34 patients (autologous HSCT = 10, allogeneic HSCT = 24) were sufficient for analysis. The World Health Organization equation adequately approximated MEE only on day 14 after HSCT. At all other time-points, measured energy expenditure was significantly less than estimated energy expenditure obtained by using the WHO equation (applicable to all patients), the Seashore equation (for patients <15 years of age; n = 19), or the Harris-Benedict equation (for patients > or =15 years of age; n = 15). The median measured energy expenditure varied significantly over the study period and was greatest on day 14 after HSCT. Until accurate equations have been identified for estimating these patients' needs, the use of indirect calorimetry may be medically warranted.

Second malignancy after treatment of childhood non-Hodgkin lymphoma.

BACKGROUND: The objective of this report was to determine the cumulative incidence of and risk factors for second malignancy and the competing risk of death due to any other cause among patients who were treated for childhood non-Hodgkin lymphoma (NHL). METHODS: The authors retrospectively reviewed a cohort of 497 patients with NHL who were treated at St. Jude Children's Research Hospital between 1970 and 1997. RESULTS: A second malignancy developed in 16 patients (9 patients with solid tumors and 7 patients with secondary acute myeloid leukemia [AML]). This number was 10.8-fold (95% confidence interval, 6.1-16.9) higher than the 1.48 patients projected for the general population by SEER Cancer Statistics. The estimated cumulative incidence rate of second malignancy was 2.1% +/- 0.7% at 10 years after diagnosis of NHL and increased to 4.8% +/- 1.3% at 20 years after diagnosis. The cumulative incidence rate of second malignancy was least among patients with small noncleaved cell lymphoma (0.5% +/- 0.5% at 20 years), higher among patients with large cell lymphoma (5.8% +/- 3.3% at 20 years), and highest among patients with lymphoblastic lymphoma (10.9% +/- 3.6% at 20 years; P = 0.002 for overall comparison). Exposure to epipodophyllotoxins was a risk factor for the development of secondary AML (P < 0.001). The cumulative incidence rate of death due to other causes was significantly less for patients who were treated after June 1978 (19.9% +/- 2.2% at 10 years) compared with patients who were treated earlier (55.6% +/- 4.2% at 10 years; P < 0.001), whereas the risk of second malignancy was similar for these two eras. CONCLUSIONS: Survivors of childhood NHL, especially those with lymphoblastic histology, are at a greater risk of developing a second malignancy compared with the general population. The incidence rate of second malignancy has remained unchanged despite a recent decline in the risk of death related to primary NHL or earlier treatment complications.

Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia.

BACKGROUND: Many antileukaemic agents or their metabolites are inactivated by liver enzymes. Most anticonvulsant drugs induce drug-metabolising enzymes and thereby increase the clearance of anticancer agents. We investigated whether anticonvulsants compromise the efficacy of cancer chemotherapy. METHODS: We identified whom of 716 children treated consecutively for acute lymphoblastic leukaemia at a single academic hospital in the USA between 1984 and 1994 received treatment for 30 days or longer with anticonvulsants (phenytoin, phenobarbital, carbamazepine, or a combination) at the same time as antileukaemic therapy. Cox's proportional-hazards models were used to assess the prognostic significance of anticonvulsants on event-free survival and risk of haematological and central-nervous-system (CNS) relapse, with stratification for treatment protocol. FINDINGS: 40 (5.6%) of 716 patients received anticonvulsants. Use of these drugs was associated with age over 10 years (p=0.003), non-hyperdiploid leukaemia (p=0.031), and T-cell immunophenotype (p=0.022). After adjustment for age and ploidy, anticonvulsant therapy was significantly related to worse event-free survival (hazard ratio 2.67 [95% CI 1.50-4.76]; p=0.0009), haematological relapse (3.40 [1.69-6.88]; p=0.0006), and CNS relapse (2.90 [1.01-8.28]; p=0.047) among the 566 patients with B-lineage leukaemia. No such associations were seen among the 114 patients with T-cell leukaemia (p=0.61, 0.35, and 0.53, respectively). Faster clearance of teniposide (p=0.0001) and methotrexate (p=0.051), but not cytarabine (p=0.26) was found among patients receiving anticonvulsants. INTERPRETATION: Long-term anticonvulsant therapy increases the systemic clearance of several antileukaemic agents and is associated with lower efficacy of chemotherapy. Alternatives to enzyme-inducing anticonvulsants should be prescribed for patients receiving chemotherapy for acute lymphoblastic leukaemia.

Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia.

By using rapid flow cytometric techniques capable of detecting one leukemic cell in 10(4) normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, > or = 0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P < .001); patients with high levels of MRD at the end of the induction phase (> or = 1%) or at week 14 of continuation therapy (> or = 0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% +/- 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% +/- 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD(+) patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients. (Blood. 2000;96:2691-2696)

Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital.

We present the long-term results of three consecutive clinical trials (Total Therapy studies 11, 12 and 13A) conducted for children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1984 and 1994. In study 11 (1984-1988), the overall event-free survival rates (+/-1 s.e.) were 71.8 +/- 2.4% and 69.3 +/- 2.4%, and the cumulative risks of isolated central nervous system (CNS) relapse 5.6 +/- 1.2% and 5.9 +/- 1.3%, at 5 and 10 years, respectively. In study 12 (1988-1991), event-free survival rates were 67.6 +/- 3.4% and 61.5+/- 9.0%, and isolated CNS relapse rates were 10.4 +/- 2.3% and 10.4 +/- 2.3%, respectively. Early intensive intrathecal therapy in study 13A (1991-1994) has yielded a very low 5-year isolated CNS relapse rate of 1.2 +/- 0.9%, boosting the 5-year event-free survival rate to 76.9 +/- 3.3%. Factors consistently associated with an adverse prognosis included male sex, infant or adolescent age group, leukocyte count >100 x 10(9)/l, nonhyperdiploidy karyotype and poor early response to treatment. Risk classification based on age and leukocyte count had prognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions or modifications for patients with specific genetic abnormalities or persistent minimal residual leukemia may further improve long-term results.

Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus.

BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes. METHODS: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided. RESULTS: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.

High incidence of secondary brain tumours after radiotherapy and antimetabolites.

BACKGROUND: Brain tumours rarely occur in survivors of childhood acute lymphoblastic leukaemia after cranial radiotherapy. An unusually high frequency of brain tumours seen among children enrolled in one of our leukaemia treatment protocols, Total Therapy Study XII, prompted us to identify the potential causes of this complication. METHODS: We assessed clinical, biological, and pharmacokinetic features in all 52 children who received prophylactic cranial radiotherapy. We compared the cumulative incidence of brain tumours between subgroups, and with that of 421 children who received radiotherapy in previous studies. FINDINGS: The incidence of brain tumours among irradiated children (six of 52, 12.8% [SE 5.0]) was high compared with patients in the same study who did not receive radiotherapy (none of 101; p=0.0008) and with other protocols that included cranial radiotherapy (p<0.0001). Of the six children, four had erythrocyte concentrations of thioguanine nucleotide metabolites higher than the 70th percentile for the entire cohort, and three had a genetic defect in thiopurine catabolism. The 8-year cumulative incidence of brain tumour among children with defective versus wild-type thiopurine methyltransferase phenotype was 42.9% (SE 20.6) versus 8.3% (4.7; p=0.0077). This protocol differed from previous protocols, in that more intensive systemic antimetabolite therapy was given before and during radiotherapy. INTERPRETATION: These data support the elimination of prophylactic radiotherapy for acute lymphoblastic leukaemia except in patients at high risk of central-nervous-system relapse. Underlying genetic characteristics and treatment variables may be associated with an increased risk of radiation-associated brain tumours.

Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia.

6-Mercaptopurine (6MP) and methotrexate are the backbone of continuation therapy for childhood acute lymphoblastic leukemia (ALL). In studies of oral 6MP and methotrexate, indices of chronic systemic exposure to active metabolites of these agents, namely, red blood cell (RBC) concentrations of methotrexate polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have positively correlated with event-free survival (EFS). Our objective was to evaluate whether MTXPGs, TGNs, and the dose intensity of administered methotrexate and 6MP were prognostic in the setting of a treatment protocol in which all treatment was coordinated through a single center, and the weekly doses of methotrexate were given parenterally. On protocol Total XII, 182 children achieved remission and received weekly methotrexate 40 mg/m2 parenterally and daily oral 6MP, interrupted every 6 weeks during the first year by pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurine methyltransferase (TPMT) measurements, along with complete dose intensity information (dose received divided by protocol dose per week) for 19,046 weeks of 6MP and methotrexate, were analyzed. In univariate analyses, only higher dose intensity of 6MP and of weekly methotrexate were significant predictors of overall EFS (P =.006 and. 039, respectively). The occurrence of neutropenia was associated with worse outcome (P =.040). In a multivariate analysis, only higher dose intensity of 6MP (P =.020) was a significant predictor of EFS, with lower TPMT activity (P =.096) tending to associate with better outcome. 6MP dose intensity was also associated (P =.007) with EFS among patients with homozygous wild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to missed weeks of therapy and not to reductions in daily dose. We conclude that increased dose-intensity of oral 6MP is an important determinant of EFS in ALL, particularly among those children with a homozygous wild-type TPMT phenotype. However, increasing intensity of therapy such that neutropenia precludes chemotherapy administration may be counterproductive.

Low frequency of TEL-AML1 in relapsed acute lymphoblastic leukemia supports a favorable prognosis for this genetic subgroup.

The long-term outcome of children with TEL-AML1-positive acute lymphoblastic leukemia (ALL) is uncertain. Although studies of newly diagnosed cases have indicated that the TEL-AML1 fusion confers a favorable prognosis, analyses of relapsed cases have suggested that this may not be true. Because of treatment implications for this subgroup of patients, we have now analyzed 49 cases of relapsed ALL for the presence of TEL-AML1. Only 10% of these cases expressed the fusion, compared to 20-25% of newly diagnosed ALL cases. Additional follow-up of the cohort of 48 newly diagnosed patients with the TEL-AML1 fusion previously reported showed that the 10-year cumulative risk of relapse was 9 +/- 5% (s.e.). Together, these results suggest an excellent outcome for TEL-AML1-positive ALL.

Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children's Research Hospital.

PURPOSE: To evaluate the incidence of and potential risk factors for second malignant neoplasms of the brain following treatment for childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: The study population consisted of 1,612 consecutively enrolled protocol patients treated on sequential institutional protocols for newly diagnosed ALL at St Jude Children's Research Hospital (SJCRH) between 1967 and 1988. The median follow-up duration is 15.9 years (range, 5.5 to 29.9 y). RESULTS: The cumulative incidence of brain tumors at 20 years is 1.39% (95% confidence interval [CI], 0.63% to 2.15%). Twenty-two brain tumors (10 high-grade gliomas, one low-grade glioma, and 11 meningiomas) were diagnosed among 21 patients after a median latency of 12.6 years (high-grade gliomas, 9.1 years; meningiomas, 19 years). Tumor type was linked to outcome, with patients who developed high-grade tumors doing poorly and those who developed low-grade tumors doing well. Risk factors for developing any secondary brain tumor included the presence of CNS leukemia at diagnosis, treatment on Total X therapy, and the use of cranial irradiation, which was dose-dependent. Age less than 6 years was associated with an increased risk of developing a high-grade glioma. CONCLUSION: This single-institution study, with a high rate of long-term data capture, demonstrated that brain tumors are a rare, late complication of therapy for ALL. We report many more low-grade tumors than others probably because of exhaustive long-term follow-up evaluation. The importance of limiting cranial radiation is underscored by the dose-dependent tumorigenic effect of radiation therapy seen in this study.

Reappraisal of the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia.

PURPOSE: To reassess the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: We prospectively studied 334 newly diagnosed cases of this disease, using a comprehensive panel of antibodies that represented five myeloid cluster groups (CD13, CD14, CD15, CD33, and CD65). Blast cells were tested for ETV6 and MLL rearrangement using Southern blot analysis. RESULTS: CD13 was expressed in 13.7% of cases, CD14 in 1%, CD15 in 6.6%, CD33 in 16%, and CD65 in 9.7%. Approximately one third of cases (31.4%) expressed one or more of these antigens (B-cell precursor, 31.9%; T-cell, 28.8%), while 10.5% expressed two or more (B-cell precursor, 11.3%; T-cell, 6.1%). Among the B-cell precursor leukemias, myeloid-associated antigen expression was significantly associated with a lack of hyperdiploidy and rearrangements of ETV6 or MLL gene. Most of the cases with MLL rearrangements (82%) expressed CD65, CD15, and CD33, either alone or in combination, whereas 48% of those with a rearranged ETV6 gene expressed CD13, CD33, or both. Myeloid-associated antigen expression did not correlate with event-free survival, whether the analysis was based on any of the five antigens in our panel or on the three more commonly tested antigens (CD13, CD33, and CD65). Importantly, this finding was not affected by exclusion of patients with ETV6 or MLL gene rearrangements. CONCLUSION: Even though blast cell expression of myeloid-associated antigen expression shows significant associations with specific genetic abnormalities, it lacks prognostic value in childhood ALL.

Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia.

Central nervous system (CNS) relapse has been an obstacle to uniformly successful treatment of childhood acute lymphoblastic leukemia (ALL) for many years. We therefore intensified intrathecal chemotherapy (simultaneously administered methotrexate, hydrocortisone, and cytarabine) for 165 consecutive children with newly diagnosed ALL enrolled in Total Therapy Study XIIIA from December 1991 to August 1994. The 64 patients (39%) who had 1 or more blast cells in cytocentrifuged preparations of cerebrospinal fluid at diagnosis, with or without associated higher-risk features, received additional doses of intrathecal chemotherapy during remission induction and the first year of continuation treatment. Patients with higher-risk leukemia, regardless of cerebrospinal fluid findings, also received additional doses of intrathecal chemotherapy during the first year of continuation treatment. Cranial irradiation was reserved for patients with higher-risk leukemia (22% of the total). The 5-year cumulative risk of an isolated CNS relapse among all 165 patients was 1.2% (95% confidence interval, 0% to 2.9%), whereas that of any CNS relapse was 3.2% (0. 4% to 6.0%). The probability of surviving for 5 years without an adverse event of any type was 80.2% +/- 9.2% (SE). Our results suggest that early intensification of intrathecal chemotherapy will reduce the risk of CNS relapse to a very low level in children with ALL, securing a higher event-free survival rate overall.

Minimal residual disease after intensive induction therapy in childhood acute lymphoblastic leukemia predicts outcome.

We investigated the level of minimal residual disease (MRD) in 26 children with B-lineage acute lymphoblastic leukemia (ALL) after intensive induction therapy. A quantitative semi-nested polymerase chain reaction (PCR) detecting the clone-specific rearranged immunoglobulin heavy chain genes was developed to improve sensitivity and specificity of amplification. In all patients, one leukemic cell could be detected in a background of 10(5) normal blood mononuclear cells. All patients investigated were in complete remission at the end of induction therapy as evaluated by morphologic criteria. Nineteen patients (73%) had no detectable residual leukemic cells using the sensitive semi-nested PCR. Seven patients (27%) were PCR positive. Three had a low level (<2 x 10(-5) leukemic cells per bone marrow cell), while four patients had a high level (>2 x 10(5)) of detectable residual leukemic cells. All patients with low or undetectable levels of residual leukemia remained in complete remission at a median of 63 months from diagnosis (range 40-80 months), while all four patients with a high level of residual leukemia subsequently relapsed at a median of 21 months from diagnosis (range 13-37 months). The patient groups with undetectable or low, and high level of MRD did not differ significantly in other clinical or genetic features with prognostic significance. We conclude that the level of MRD at the end of the intensive induction therapy period is predictive of outcome in childhood B lineage ALL. If confirmed by large prospective studies, the level of MRD might be useful in stratifying patients into high and low risk categories.

Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia.

BACKGROUND: The clinical significance of submicroscopic levels of leukaemic cells in bone-marrow aspirates from children with acute lymphoblastic leukaemia (ALL) remains controversial. We prospectively determined the frequency and prognostic importance of minimal residual disease detected by a rapid immunological assay in bone-marrow aspirates of children with ALL. METHODS: 158 children with newly diagnosed ALL received 6 weeks of remission-induction chemotherapy. Once complete clinical remission was attained the patients received 2 weeks of consolidation therapy followed by continuation therapy. Bone-marrow aspirates were collected after induction therapy and during weeks 14, 32, and 56 of continuation therapy, and then at 120 weeks (end of therapy). Cells with leukaemia-associated immunophenotypes were investigated by multiparameter flowcytometry capable of detecting one leukaemic cell among 10,000 normal cells. FINDINGS: The proportion of patients with detectable leukaemic cells was 23% at remission induction and 17% at week 14 of continuation therapy, decreasing to 5% and 4% at weeks 32 and 56. None of the 65 samples examined at completion of therapy (week 120) showed evidence of disease. Detectable residual disease at the end of remission induction correlated with adverse genetic abnormalities--the Philadelphia chromosome and MLL gene rearrangements--but not with other presenting features. Detectable leukaemia was associated with subsequent relapse regardless of the time at which bone-marrow samples were examined (p < 0.002 for all comparisons). For example, 3-year cumulative incidence (SE) of relapse in patients with and without detectable leukaemia at remission induction was 32.5% (10.6) and 7.5% (4.0), respectively (p < 0.001); for tests done at week 14, it was 42.1% (14.6) and 6.6% (3.5), p < 0.001. These correlations remained significant after adjusting for adverse presenting features. A higher degree of marrow infiltration by leukaemic cells (> or = 0.1%) in week 14 samples identified a subset of patients with an especially poor prognosis. INTERPRETATION: Immunological detection of residual leukaemic cells at any point in the treatment course is a powerful predictor of relapse in children with ALL. Alternative treatment should be considered for cases with persistent disease beyond the first 3 months of continuation therapy.

Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts.

To substantiate the reported sensitivity of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) to St Jude-type multiagent chemotherapy and to identify means of selecting patients most likely to benefit from such treatment, we analyzed the clinical and biologic characteristics of 12 patients with classic Ph+ ALL who were treated in either of two total therapy programs at St Jude Children's Research Hospital (1989-1994). Event-free survival estimates for this cohort were compared with historical data on 11 patients from an earlier total therapy study (Lancet 1994; 343: 331-332). The prognostic importance of age, white blood cell count and other presenting features was assessed by the logrank test in all 23 patients. Complete remissions were induced in 92% of the patients treated since 1989, compared with 82% of the historical control group (P > 0.05). There was essentially no difference in event-free survival between the study group and historical controls (4-year Kaplan-Meier estimates, 33 +/- 19% s.e. vs 36 +/- 13%). Further analysis of potentially informative risk factors identified a good-prognosis subgroup defined by an initial white blood cell count of < or =25 x 10(9)/l and a 4-year event-free survival of 73 +/- 19%. In conclusion, intensive multiagent chemotherapy offers an attractive therapeutic option for children and adolescents with Ph+ ALL and low presenting leukocyte count.

Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Recombinant human granulocyte colony-stimulating factor PO1 CA-20180ilgrastim) hastens the recovery from neutropenia after P30 CA-21765emotherapy, but its role in the management of childhood leukemia is unclear. METHODS: We randomly assigned 164 patients with acute lymphoblastic leukemia (age range, 2 months to 17 years) to receive placebo or G-CSF (10 microg per kilogram of body weight per day subcutaneously), beginning one day after the completion of remission-induction therapy and continuing until the neutrophil count was greater than or equal to 1000 per cubic millimeter for two days. The clinical and laboratory effects of this therapy were documented for 21 days. The area under the plasma G-CSF concentration-time curve was measured on days 1 and 7 in both groups. RESULTS: Responses to the growth factor could be assessed in 148 patients (73 in the G-CSF group and 75 in the placebo group). G-CSF treatment did not significantly lower the rate of hospitalization for febrile neutropenia (58 percent in the G-CSF group vs. 68 percent in the placebo group; relative risk, 0.85; 95 percent confidence interval, 0.59 to 1.16), increase the likelihood of event-free survival at three years (83 percent in both groups), or decrease the number of severe infections (five in the G-CSF group vs. six in the placebo group). Patients treated with G-CSF had shorter median hospital stays (6 days vs. 10 days, P=0.011) and fewer documented infections (12 vs. 27, P=0.009). The median total costs of supportive care were similar in the G-CSF and placebo groups ($8,768 and $8,616, respectively). Among patients who did not have febrile neutropenia during the first week of G-CSF or placebo injections, higher systemic exposure to the growth factor on day 7 was significantly related to a lower probability of subsequent hospitalization (P=0.049). CONCLUSIONS: G-CSF treatment had some clinical benefit in children who received induction chemotherapy for acute lymphoblastic leukemia, but it did not reduce the rate of hospitalization for febrile neutropenia, prolong survival, or reduce the cost of supportive care.

TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance.

PURPOSE: TEL gene rearrangements due to the 12;21 chromosomal translocation are the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a B-precursor immunophenotype. The limited number of clinically useful genetic markers in this leukemia subtype prompted us to assess TEL status as a predictor of treatment outcome. PATIENTS AND METHODS: We determined the status of the TEL gene (rearranged or germline) in 188 cases of B-precursor acute leukemia using Southern blot analysis and related the findings to event-free survival. All comparisons of outcome were stratified by treatment regimen, risk classification, age, and leukocyte count. RESULTS: Forty-eight patients (26%) had a rearranged TEL gene. At 5 years of follow-up, an estimated 91% +/- 5% (SE) of this group were event-free survivors, compared with only 65% +/- 5% of the group with germline TEL (stratified log-rank P = .011). For nonhyperdiploid patients, the odds ratio of an adverse event in the germline TEL group to that for the rearranged TEL group was 4.06 (95% confidence interval, 1.86 to 8.84). The relationship of TEL rearrangement to a favorable prognosis was independent of recognized good-risk features in B-precursor leukemia, including age, initial leukocyte count, and hyperdiploidy. CONCLUSION: Rearrangement of the TEL gene distinguishes a large subset of children with favorable-prognosis B-precursor leukemia who cannot be identified by standard prognostic features. It may be possible to treat these patients less aggressively without loss of therapeutic efficacy.