High concordance from independent studies by the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative.

Chromosome aberrations have a major role in pediatric acute lymphoblastic leukemia (ALL) risk assignment. The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) independently assessed the significance of trisomy for chromosomes 4, 10, and 17 in National Cancer Institute (NCI) Standard- and High-Risk ALL. Data from 1582 (CCG) and 3902 (POG) patients were analyzed. Eight-year event-free survivals (EFS) of 91% (CCG) and 89% (POG) (P < 0.001) were achieved in patients assigned to NCI Standard Risk whose leukemic cells had simultaneous trisomies 4, 10, and 17. Both groups showed the degree of favorable prognostic importance increased with the actual number of favorable trisomies. POG analyses also demonstrated hyperdiploidy (> or =53 chromosomes) was less of an independently significant prognostic factor in the absence of these key trisomies. This finding supported conclusions from previous CCG and POG studies that specific trisomies are more important than chromosome number in predicting outcome in pediatric B-precursor ALL. In NCI Higher Risk patients, the number of favorable trisomies was not prognostically significant, but showed the same trend. Moreover, specific trisomies 4, 10, and 17 remain associated with favorable prognosis in Standard-Risk B-precursor ALL, even in the context of very different treatment approaches between the groups.

Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group.

PURPOSE: To determine the incidence, risk factors, and morbidity for osteonecrosis (ON) in children with acute lymphoblastic leukemia (ALL) treated with intensive chemotherapy including multiple, prolonged courses of corticosteroid. PATIENTS AND METHODS: The occurrence of symptomatic ON was investigated retrospectively in 1, 409 children ages 1 to 20 years old receiving therapy for high-risk ALL on Children's Cancer Group (CCG) protocol CCG-1882. RESULTS: ON was diagnosed in 111 patients (9.3% +/- 0.9%, 3-year life-table incidence). The incidence was higher for older children (> or = 10 years: 14.2% +/- 1.3% v < 10 years: 0.9% +/- 0.4%; P: <.0001), especially females 10 to 15 years old and males 16 to 20 years old (19.2% +/- 2.3% and 20.7% +/- 4.7%, respectively). In patients 10 to 20 years old, the incidence of ON was higher for females versus males (17.4% +/- 2.1% v 11.7% +/- 1.6%, respectively; P: =.03) and for patients randomized to receive two 21-day dexamethasone courses versus one course (23.2% +/- 4.8% v 16.4% +/- 4.3%, respectively; P: =.27). Among ethnic groups, whites had the highest incidence and blacks the lowest, with other groups intermediate (16.7% +/- 1.4% v 3.3% +/- 2.3% v 6.7% +/- 2.2%, respectively; P: =.003). There was no difference in event-free survival in patients with or without ON. ON was diagnosed within 3 years of starting ALL therapy in all but one patient, involved weight-bearing joint(s) in 94% of patients, and was multifocal in 74% of patients. Symptoms of pain and/or immobility were chronic in 84% of patients, with 24% having undergone an orthopedic procedure and an additional 15% considered candidates for surgery in the future. CONCLUSION: Children ages 10 to 20 years who receive intensive ALL therapy, including multiple courses of corticosteroid, are at significant risk for developing ON.

Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children's Cancer Group.

PURPOSE: Compared with previous Children's Cancer Group (CCG) acute lymphoblastic leukemia (ALL) trials, therapy based on the Berlin-Frankfurt-Munster (BFM) 76 trial has effected an improvement in event-free survival (EFS). In an attempt to improve EFS further, CCG investigators formulated an augmented BFM (A-BFM) regimen that provides prolonged, intensified postinduction chemotherapy relative to the CCG-modified BFM regimen. PATIENTS AND METHODS: We tested A-BFM in 101 patients with ALL and unfavorable presenting features that showed slow early response (SER) to induction therapy who attained remission on day 28. Their outcome was compared with that of 251 concurrent patients with unfavorable presenting features, a rapid early response to therapy (RER), and remission by day 28, treated with CCG-BFM with or without cranial radiation (CRT). RESULTS: The 4-year EFS rate from the end of induction for SER patients treated with A-BFM was 70.8% +/- 4.6%. Seventeen patients remain in continuous remission beyond 5 years. Vincristine (VCR) neurotoxicity developed in 50% of patients, but was rarely debilitating. Allergies to Escherichia coli L-asparaginase (L-ASP) occurred in 35% of patients. Avascular necrosis of bone (AVN) developed in 9% of patients. In comparison, a concurrent RER group treated with standard BFM +/- CRT had a 4-year EFS rate of 73.1% +/- 4.6%. CONCLUSION: The toxicity of A-BFM is significant, but acceptable. Compared with historical control SER patients treated with CCG-modified BFM, A-BFM therapy appears to produce a significant improvement in EFS. This is the first study to show that intensive chemotherapy, as given in the A-BFM regimen, can abrogate the adverse prognostic significance of SER.

Randomized study of 3 years versus 5 years of chemotherapy in childhood acute lymphoblastic leukemia.

Between 1972 and 1975 the Children's Cancer Study Group conducted two clinical trials for the treatment of newly diagnosed patients with acute lymphoblastic leukemia. Upon achieving 3 yr of continuous complete remission, 316 children and young adults were randomly allocated either to discontinue chemotherapy or to continue chemotherapy for an additional 24 mo. With a median follow-up from the time of randomization of 50 mo, those patients who received 3 yr of therapy have demonstrated a statistically non-significant yet higher incidence of bone marrow relapse as compared to those patients treated for 5 yr (p = 0.09). However, the proportion of patients surviving 5 yr from randomization is 93% for the 3-yr treatment group and 89% for the 5-yr treatment group (p = 0.27). No significant difference was observed between the randomized groups for the occurrence of testicular relapse (p = 0.12), central nervous system relapse (p = 0.17), or first occurrence of relapse or death (p = 0.24). The relapse-free survival of patients treated for 5 yr as compared to those treated for 3 yr was not significantly higher in males (81% versus 75%, p = 0.14) or females (89% versus 89%, p = 0.95). This randomized study did not demonstrate a significant difference between treatment for either 3 or 5 yr.

Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy.

The optimal management for patients with stage II neuroblastoma has not yet been established. In order to determine the impact of adding chemotherapy and/or radiation therapy to surgery, we reviewed by questionnaire 156 patients with stage II neuroblastoma treated by 28 Childrens Cancer Study Group (CCSG) institutions from 1978 to 1985. Survival and progression-free survival (PFS) were analyzed by life-table methods with respect to age at diagnosis, site and size of primary tumor, spinal cord involvement, extent of initial resection, and treatment in addition to surgery. The overall 5-year survival was 96%; the PFS was 90%, similar to previous CCSG studies. Age at diagnosis had a small impact on PFS, with 92% PFS for patients less than 2 years of age at diagnosis, and 84% for those greater than 2 (P = .10). The only site with an adverse outcome was the head and neck (n = 11), with a PFS of 68% compared with 93% for the remaining sites (P = .02). Size of primary and intraspinal extension of primary did not affect PFS. The extent of resection and subsequent treatment with radiation therapy and/or chemotherapy did not affect the PFS. The outcome for 75 patients treated with surgery alone (6-year PFS, 89%) was not significantly different from that of 66 patients receiving radiation therapy (6-year PFS, 94%). There was no significant difference between 40 patients with gross or microscopic residual disease treated with surgery alone (PFS, 92%) and 59 patients with residual disease who also received radiation (PFS, 90%). Five of seven patients who progressed after surgery alone have been salvaged with further therapy and are now free of disease. One survives with disease, so that the 6-year survival is 98% for those treated initially with surgery alone, compared with 95% for those receiving radiation therapy and/or chemotherapy. These data suggest that surgery alone, even if complete resection is not achieved, is sufficient initial therapy for stage II neuroblastoma. The data also identify another stage of neuroblastoma, in addition to stage IV-S, for which almost all patients have a favorable prognosis because their tumor may be biologically limited in growth.

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.

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.

The effect of initial management of hyperleukocytosis on early complications and outcome of children with acute lymphoblastic leukemia.

Data were collected from 124 patients with newly diagnosed acute lymphoblastic leukemia (ALL) and WBC greater than 200,000/microL seen at institutions affiliated with the Children's Cancer Study Group (CCSG) from April 1981 to May 1983. The presenting characteristics, initial management, early complications, and outcome were reviewed. All the children received vigorous intravenous (IV) hydration, alkalinization of the urine, and allopurinol. Thirty-two patients were started on full therapy with no additional measure. One or more special measures believed to reduce the complications of leukostasis and blast cell lysis were administered to 92 patients as follows: small initial doses of prednisone, 63; emergency cranial irradiation, 26; exchange transfusion, 21; and leukopheresis, 19. The incidence of CNS hemorrhage was only 3% (4/124). Seven patients expired during induction and four failed to achieve a remission by day 28. Nineteen patients (15%) had documented bacterial or fungal sepsis. Mild to moderate electrolyte abnormalities occurred in 29 patients: three patients required renal dialysis. Pretreatment with small doses of prednisone did not decrease the incidence of electrolyte abnormalities in those patients when compared with patients who received full chemotherapy. The event-free survival (EFS) for the 106 patients treated on one of the three intensive pilot studies is 55% at 36 months. On multivariate analysis the two significant adverse prognostic factors were massive splenomegaly (P = .02) and WBC count greater than 600,000/microL (P = .05). In conclusion, in patients with hyperleukocytosis the complications of blast cell lysis and leukostasis were manageable with acceptable morbidity and minimal mortality in a group of patients treated with vigorous hydration, allopurinol, and alkalinization of the urine before beginning chemotherapy. Selected patients with severe hyperuricemia and renal dysfunction may benefit from leukopheresis. No beneficial role was demonstrated for the use of small initial doses of prednisone or emergency cranial irradiation.

Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group has assessed serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and pubertal development in 97 long-term female survivors of childhood acute lymphoblastic leukemia (ALL). All patients received identical induction and maintenance therapy with either 18 or 24 Gy of radiation therapy (RT) to one of the following fields: cranial, craniospinal, or craniospinal plus 12 Gy abdominal RT including the ovaries. Thirty-six percent (35 patients) were found to have above normal levels of FSH and/or LH. The percentages of elevated values for RT fields were 93% for craniospinal plus abdominal RT, 49% for craniospinal RT, and 9% for cranial RT (P less than .001). A dose-response relationship was observed between 18 Gy and 24 Gy in females receiving only craniospinal RT (P = .01). Craniospinal plus abdominal RT and abnormal FSH/LH levels were significantly associated with lack of pubertal development and delayed onset of menses. Duration of maintenance chemotherapy was not associated with abnormal gonadotropin levels or the development of secondary sexual characteristics. Additional follow-up of this cohort is needed to establish the ultimate pubertal development and fertility of these patients.

Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group.

The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.

Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen.

During the period 1976-1981, 3241 children were enrolled on three major studies of acute lymphoblastic leukemia by participating institutions of the Children's Cancer Study Group. Each study included a different method of central nervous system (CNS) prophylaxis: (1) standard therapy with cranial irradiation, 2400 rads, and intrathecal methotrexate at 12 mg/m2 six times during consolidation (CCG-141); (2) a modification of CCG-141 in which the intrathecal methotrexate was initiated during induction (CCG-141A); and (3) a reduced cranial irradiation dose of 1800 rads with intrathecal methotrexate given at the same frequency as a CCG-141A, with or without maintenance intrathecal methotrexate, but with a dosage regimen derived from CNS volume considerations rather than based on body surface area (CCG-160 series). Strategy 3, a change in the intrathecal methotrexate dosage, has resulted in the lowest incidence of CNS leukemia to date (p less than 0.007). The cumulative 3-yr CNS relapse rate has decreased from 8%-10% to 2%-5% in average-risk patients (p less than 0.02; life table estimate) and from 23%-27% to 6% in high-risk patients (p less than 0.0002; life table estimate), despite a reduction in the cranial irradiation dose from 2400 to 1800 rads. Maintenance intrathecal chemotherapy has had a marginal effect among patients randomized to receive this additional therapy (p = 0.06). The overall outcome has been an increase in the continuous complete remission rate (p = 0.04) but not in the estimated 3-yr continuous hematologic remission or survival rates.

Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group.

PURPOSE: Intensified intrathecal (i.t.) chemotherapy without cranial radiation therapy (CRT) prevents CNS relapse in children with low-risk and intermediate-risk acute lymphoblastic leukemia (ALL). In the current study, high-risk ALL patients who achieved a rapid early response (RER) to induction chemotherapy were randomized to receive intensive systemic chemotherapy and presymptomatic CNS therapy that consisted of either i.t. methotrexate (MTX) and CRT or intensified i.t. MTX alone. PATIENTS AND METHODS: Children (n = 636) with high-risk ALL (aged 1 to 9 years and WBC count > or = 50,000/microL or age > or = 10 years, excluding those with lymphomatous features) who achieved an RER (< or = 25% marrow blasts on day 7) to induction therapy and lacked CNS disease at diagnosis were randomized to receive systemic therapy with either i.t. MTX and CRT (regimen A, n = 317) or intensified i.t. MTX alone (regimen B, n = 319). RESULTS: Interim analysis in July 1993 revealed 3-year event-free survival (EFS) estimates of 82.1% +/- 4.0% (SD)and 70.4% +/- 4.2% for patients treated on regimens A and B, respectively (P = .004). As of January 1996, outcome had changed: 5-year EFS estimates were 69.1% +/- 3.4% and 75.0% +/- 2.7% for regimens A and B, respectively (P = 0.50). Marrow relapses comprised 57 events on regimen A and 43 events on regimen B. Fewer late events occurred on regimen B. CONCLUSION: For high-risk pediatric ALL patients who show an RER to induction therapy and are treated with systemic Children's Cancer Group (CCG)-modified Berlin-Frankfurt-Munster (BFM) chemotherapy, presymptomatic CNS therapy that consists of either i.t. MTX plus CRT or intensified i.t. MTX alone results in a similar 5-year EFS outcome. Furthermore, intensified i.t. MTX may protect against late bone marrow relapse.

A comparison of four staging systems for localized and regional neuroblastoma: a report from the Childrens Cancer Study Group.

Four major staging systems have been used to estimate the prognosis for children with local and regional neuroblastoma (NBL). Data obtained at diagnosis for 251 neuroblastoma patients from two Childrens Cancer Study Group (CCSG) studies were analyzed according to staging systems of the CCSG, St Jude Children's Research Hospital, the Pediatric Oncology Group (POG), and the Union Internationale Contre le Cancer (UICC) tumor-nodes-metastasis (TNM) system. The most significant variables were found to be age, tumor stage, extent of tumor removal, transgression of the midline by tumor infiltration, and site of primary tumor. Involvement of lymph nodes per se was not a bad prognostic sign unless associated with extension beyond the midline, the latter being the single most important prognostic variable. All four staging systems had value for prognostication and all identified with accuracy the low stage patient (stage I, stage A) who fares well (greater than or equal to 87% survival). The CCSG definition of stages II and III disease discriminated prognostic groups best among the remaining patients, and was able to identify the child with local-regional NBL with poor survival. The estimated 5-year survival rates for children with regional tumor (stage III, IIIA[N]), according to the four systems were 44%, 74%, 74%, and 74% for the CCSG, St Jude, POG, and UICC methods, respectively. We conclude that all four staging systems effectively define good-prognosis patients with localized disease but that the CCSG staging system most accurately identifies patients with regional tumor who have a poor outcome.

The prognostic value of testicular biopsy in childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

One of the objectives of Childrens Cancer Study Group (CCSG) study 141 (CCG-141) was to determine the frequency of occult testicular leukemia (TL) after 3 years of disease-free survival (DFS) and to retreat boys with occult TL to prolong their subsequent DFS. Of the 494 boys entered on study, 255 (51.6%) were in complete continuous remission (CCR) 3 years after entering remission and an additional eight were in CCR 3 years after localized extramedullary relapse and retreatment; 263 boys were eligible for testicular biopsy. Elective testicular biopsy was performed on 235 (89.4%) boys. Of the 204 (86.8%) boys with negative biopsies, 175 (85.8%) remained in CCR 10 to 12 years after diagnosis and 25 (12.3%) relapsed, 11 (44%) of whom died. Isolated overt TL occurred in four (2.0%) and all remained in CCR 22+ to 60+ months after re-treatment. Of the 26 boys with occult TL, 16 (62%) remained in CCR. Ten (38%) relapsed despite local testicular irradiation and systemic re-treatment; six of the 10 died. Of the 26 boys who did not undergo biopsy, 21 (80.8%) remained in CCR; two (7.7%) developed isolated overt TL. DFS after testicular biopsy was significantly better in boys without occult TL (P = .001). Occult TL after 3 years of CCR represents aggressive minimal-residual disease and carries a worse prognosis than absence of TL. Initial treatment should be directed at obviating occult and overt testicular relapse. Conventional therapy as used in this study was suboptimal in preventing subsequent bone marrow (BM) relapse and death. If occult TR is identified during or at the end of planned therapy, a higher salvage rate may require intensified alternate therapy. As such, testicular biopsies may be clinically useful. Further investigation is limited by the relative rarity of, and the lack of identifying features in boys with occult TL.

Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children Cancer Study Group.

Testicular function was evaluated in 60 long-term survivors of childhood acute lymphoblastic leukemia (ALL). All the patients were treated on two consecutive Children Cancer Study Group protocols and received identical chemotherapy and either 18 or 24 Gy radiation therapy (RT) to one of the following fields: craniospinal plus 12 Gy abdominal RT including the gonads (group 1); craniospinal (group 2); or cranial (group 3). The median age at the time of their last evaluation was 14.5 years (range, 10.5 to 25.7), which took place a median of 5.0 years (range, 1 to 10.3) after discontinuing therapy. The incidence of primary germ cell dysfunction as judged by raised levels of follicle-stimulating hormone (FSH) and/or reduced testicular volume was significantly associated with field of RT; 55% of group 1, 17% of group 2, and 0% of group 3 were abnormal (P = .002). Leydig cell function, as assessed by plasma concentrations of luteinizing hormone (LH) and testosterone, and pubertal development, was unaffected in the majority of subjects regardless of RT field. These data indicate that in boys undergoing therapy for ALL, germ cell dysfunction is common following testicular irradiation and can occur following exposure to scattered irradiation from craniospinal RT. In contrast, Leydig cell function appears resistant to direct irradiation with doses as high as 12 Gy.

Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) CCG-160 protocol series was designed to evaluate prognostic factors in acute lymphoblastic leukemia (ALL). Patients were assigned to one of three prognostic groups based upon initial WBC count and age. To determine the optimal duration of therapy, CCG-160 patients completing 2 years of treatment in continuous remission were randomized ("late randomization") to discontinue therapy or receive another year of maintenance therapy. The prognostic significance of early response to induction therapy, as measured by the percentage of lymphoblasts in the day-14 bone marrow (d14 BM) aspirate, was evaluated in 2,516 children. For 1,490 patients with complete data, the status of the d 14 BM was a highly significant predictor of disease-free survival (DFS) by univariate and multivariate analysis (P less than .0001). The observed/expected (O/E) failure rate in patients with d14 M1 (less than 5% blasts), M2 (4% to 25% blasts), or M3 (greater than 25% blasts) BM rating who were subsequently M1 on day 28 or day 42, was .87, 1.59, and 2.30, respectively (P less than .0001). Patients with M2 or M3 d14 BM were more likely to have L2 ALL (modified French-American-British [FAB] morphologic classification), P less than .001. The significance of the d14 BM rating persisted after correction was made for WBC count and clinical prognostic groups using current CCSG criteria, except in infants less than 12 months of age. The d14 BM was also the most significant predictor of DFS in 975 patients after late randomization at 2 years following diagnosis. The O/E failure rate in patients with d14 M1, M2, or M3 BM was .88, 1.78, and 2.02, respectively (P = .0002, trend). Other significant predictors of late relapse were prognostic groups (P = .0003, trend) and initial WBC count (P = .004, trend). Predictive for both early and late relapse of ALL, early response should be monitored closely and alternative treatment regimens should be considered for slow responders.

Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group.

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study.

PURPOSE: Leukemic cells from T-lineage acute lymphoblastic leukemia (ALL) patients are thought to originate from T-lymphocyte precursors corresponding to discrete stages of T-cell ontogeny. Here we sought to determine the influence of leukemic cell apparent maturational stage on treatment outcomes in pediatric T-lineage ALL. PATIENTS AND METHODS: From 1983 through 1993, 407 pediatric T-lineage ALL patients were enrolled onto two sequential series of risk-adjusted treatment protocols of the Children's Cancer Group. In the current analysis, T-lineage ALL patients were immunophenotypically classified as follows: CD7+ CD2- CD5- pro-thymocyte leukemia (pro-TL), CD7+ (CD2 or CD5)+ CD3- immature TL, and CD7+ CD2+ CD5+ CD3+ mature TL. RESULTS: Similar induction outcomes of 91.4%, 97.1%, and 98.3% were obtained by the pro-, immature, and mature TL groups, respectively. Four-year event-free survival (EFS) was lower for pro-TL patients (57.1%; SD = 8.4%,) compared with immature and mature TL patients (68.5%; SD = 3.5%; and 77.1%; SD = 4.0%, respectively) with an overall significance of .05 (log-rank test) or .04 (log-rank trend test). Relative hazards rates (RHR) were 2.11 and 1.22 for pro-TL and immature TL versus mature TL, respectively. Highly significant differences were found for overall survival (P = .005, log-rank test; P = .009, log-rank trend test). Multivariate analysis confirmed that the prognostic influence of ontogeny grouping was independent of that of other prognostic factors. CONCLUSION: Leukemic cells of the pro-TL maturation stage identify a small subgroup of T-lineage ALL patients who have a significantly worse EFS outcome than patients whose cells are of a more mature stage of development.

Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes).

PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children's Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P<.0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P =.01), or neither trisomy (P<.0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P =.02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.