Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000.

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3+7+7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P=0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2+5) during the second induction course (5 year EFS estimates, 22 vs 27%; P=0.33). Age <2 years and leukocyte count <100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (36+/-4.7%) and for the group that received only intensive chemotherapy (35+/-4.5%) (P=0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 63+/-5.4%) and of children with Down's syndrome (5-year EFS estimate, 66+/-8.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both high-dose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 42+/-8.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial.

A prospective, randomized multicenter study was performed to evaluate the relative efficacy of two different concepts for early intensive therapy in a randomized trial of children with B-precursor acute lymphoblastic leukemia (ALL) at high risk (HR) for relapse. Four hundred and ninety eligible children with HR-ALL were randomized on the Pediatric Oncology Group (POG) 9006 phase III trial between 7 January 1991 and 12 January 1994. After prednisone (PDN), vincristine (VCR), asparaginase (ASP) and daunorubicin (DNR) induction, 470 patients received either 12 intensive parenteral treatments of intermediate dose (1 g/m2 each) methotrexate (MTX) and mercaptopurine (MP) over 24 weeks (regimen A) or 12 intensive course of alternating myelosuppressive drug combinations given over 30 weeks (regimen B). These drug combinations included MTX/MP, teniposide (VM-26)/cytosine arabinoside (AC) and VCR/PDN/DNR/AC/ASP. Central nervous system (CNS) prophylaxis was age-adjusted triple intrathecal chemotherapy. Patients with CNS disease at diagnosis were treated with craniospinal irradiation after the intensive phase. Continuation was standard doses of MTX and MP for 2 years. This trial was closed early because of an apparent early difference favoring regimen B. Results show that 470 patients achieved remission (97%). Two hundred and thirty two were randomized to regimen A and 238 to regimen B. The estimated 4-year event-free survival (EFS) for patients treated with regimen A is 61.6 % (s.e. = 3.3%) and with regimen B is 69.4% (s.e. = 3.1%), P = 0.091. Toxicities were more frequent on regimen B. In conclusion, for children with B-precursor ALL at high risk to relapse, early intensification with myelosuppressive combination chemotherapy was more toxic but produced no significant difference in EFS when compared to those treated with parenteral methotrexate and mercaptopurine.

Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) Study 8821.

The purpose of the paper was to define clinical or biological features associated with the risk for treatment failure for children with acute myeloid leukemia. Data from 560 children and adolescents with newly diagnosed acute myeloid leukemia who entered the Pediatric Oncology Group Study 8821 from June 1988 to March 1993 were analyzed by univariate and recursive partitioning methods. Children with Down syndrome or acute promyelocytic leukemia were excluded from the study. Factors examined included age, number of leukocytes, sex, FAB morphologic subtype, cytogenetic findings, and extramedullary disease at the time of diagnosis. The overall event-free survival (EFS) rate at 4 years was 32.7% (s.e. = 2.2%). Age > or =2 years, fewer than 50 x 10(9)/I leukocytes, and t(8;21) or inv(16), and normal chromosomes were associated with higher rates of EFS (P value = 0.003, 0.049, 0.0003, 0.031, respectively), whereas the M5 subtype of AML (P value = 0.0003) and chromosome abnormalities other than t(8;21) and inv(16) were associated with lower rates of EFS (P value = 0.0001). Recursive partitioning analysis defined three groups of patients with widely varied prognoses: female patients with t(8;21), inv(16), or a normal karyotype (n = 89) had the best prognosis (4-year EFS = 55.1%, s.e. = 5.7%); male patients with t(8;21), inv(16) or normal chromosomes (n = 106) had an intermediate prognosis (4-year EFS = 38.1%, s.e. = 5.3%); patients with chromosome abnormalities other than t(8;21) and inv(16) (n = 233) had the worst prognosis (4-year EFS = 27.0%, s.e. = 3.2%). One hundred and thirty-two patients (24%) could not be grouped because of missing cytogenetic data, mainly due to inadequate marrow samples. The results suggest that pediatric patients with acute myeloid leukemia can be categorized into three potential risk groups for prognosis and that differences in sex and chromosomal abnormalities are associated with differences in estimates of EFS. These results are tentative and must be confirmed by a large prospective clinical trial.

Intensification with intermediate-dose intravenous methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic leukemia: A Pediatric Oncology Group study.

PURPOSE: To determine whether early intensification with 12 courses of intravenous (IV) methotrexate (MTX) and IV mercaptopurine (MP) is superior to 12 courses of IV MTX alone for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Six hundred fifty-one eligible patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction therapy. Patients were randomized to receive intensification with IV MTX 1,000 mg/m(2) plus IV MP 1,000 mg/m(2) (regimen A) or IV MTX 1,000 mg/m(2) alone (regimen C). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and triple intrathecal therapy every 12 weeks for 2 years. RESULTS: Six hundred forty-five patients (99.1%) achieved remission. Three hundred twenty-five were assigned to regimen A and 320 to regimen C. The estimated 4-year overall continuous complete remission for patients treated with regimen A is 82.1% (SE = 2.4%) and for regimen C is 82.2% (SE = 2.6%; P =.5). No significant difference in overall outcome was shown by sex or race. Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen. CONCLUSION: Intensification with 12 courses of IV MTX is an effective therapy for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse but may be associated with an increased risk for neurotoxicity. Prolonged infusions of MP combined with IV MTX did not provide apparent advantage.

Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821.

We determined the type and frequency of chromosomal aberrations in leukemic cells of 478 children diagnosed with acute myeloid leukemia and enrolled in the Pediatric Oncology Group study 8821. Of the 478 cases, 109 (22.8%) had normal karyotypes. Chromosomal abnormalities of 280 patients (58.6%) were classified into subgroups: 11q23 abnormalities (n = 88, 18.4%), t(8;21) (n = 56, 11.7%), t(15;17) (n = 55, 11.5%), inv(16)/t(16;16) (n = 28, 5.9%), trisomy 8 alone (n = 10, 2.1%), monosomy 7 (n = 9, 1.9%), non-Down-associated trisomy 21 alone (n = 7, 1.5%), and rare recurrent chromosomal translocations (n = 27, 5.6%). The remaining 89 patients (18.6%) had miscellaneous clonal abnormalities. Overall, 84.9% of the children achieved a complete remission; the 4-year event-free survival (EFS) estimate was 33.8% +/- 2.4%. Remission rates were significantly higher (96.4%, P =.011) for patients with t(8;21) and inv(16)/t(16;16) but significantly lower (74.5%, P =.022) for those with t(15;17). The 4-year survival rate for all patients was 43.5% +/- 2.4%; for those with an inv(16)/t(16;16), 75.0% +/- 8.6%; a normal karyotype, 53.8% +/- 4.9%; a t(8;21), 51.6% +/- 7.3%; a t(15;17), 39.8% +/- 6.9%; and an 11q23 abnormality, 32.9% +/- 5.1%. Four-year EFS estimates for patients with inv(16)/t(16;16) (58.2% +/- 10.9%, P =.007), t(8;21) (45.1% +/- 7.7%, P =.014), or normal karyotypes (43.1% +/- 5.0%, P =. 012) were higher than the 4-year EFS estimate for all patients, but EFS estimates for patients with t(15;17) (19.6% +/- 8.0%, P =.033) or 11q23 abnormalities (23.8% +/- 4.8%, P =.0013) were lower. EFS estimates did not differ significantly among 11q23 subgroups. Limited analysis suggested that patients with inv(16) can be salvaged better following relapse than those with t(8;21). Thus, patients with an inv(16)/t(16;16) may have high survival rates when treated with chemotherapy alone.

Intensive alternating drug pairs after remission induction for treatment of infants with acute lymphoblastic leukemia: A Pediatric Oncology Group Pilot Study.

PURPOSE: Infants with acute lymphoblastic leukemia (ALL) often enter remission; however, they have a high rate of relapse. To prevent relapse, infants' tolerance of and benefits from early intensive rotating drug pairs as part of therapy were studied. METHODS: After prednisone, vincristine, asparaginase, and daunorubicin induction, 12 intensive treatments (ABACABACABAC) were administered in 30 weeks: A, intermediate dose methotrexate (MTX) and intermediate dose mercaptopurine (MP); B, cytosine arabinoside (Ara-C) and daunorubicin (DNR); C, Ara-C and teniposide (VM-26). Triple intrathecal chemotherapy (Ara-C, MTX, and hydrocortisone) was administered for central nervous system prophylaxis. Continuation therapy consisted of weekly MTX and daily MP for a total of 130 weeks of continuous complete remission. RESULTS: Thirty-three infants (1 year old or younger) with newly diagnosed ALL were treated. Two infants did not respond to induction, 1 died from sepsis during continuation, 1 received a bone marrow transplant, and 24 relapsed. Median time to relapse was 39 weeks. The event-free survival rate at 5 years was 17% (standard error +/- 7.7%). The most significant toxicities occurred during intensification and included fever-neutropenia and bacterial sepsis. CONCLUSION: Although early intensive rotating therapy is tolerable, the relapse-free survival rate remains poor for infants treated with the schedule on this protocol.

Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy--a Pediatric Oncology Group study.

PURPOSE: To describe the incidence of acute neurotoxicity (NT) in children with lower risk B-precursor acute lymphoid leukemia (ALL) treated with intermediate-dose methotrexate (MTX) or divided dose oral MTX with or without intravenous (i.v.) mercaptopurine (MP) and extended intrathecal triple therapy. PATIENTS AND METHODS: Thirteen hundred four patients were entered onto Pediatric Oncology Group (POG) 9005, a randomized phase III trial, between January 11, 1991 and September 1, 1994. After remission induction, patients were randomized to one of three 24-week intensification schedules: regimen A, MTX 1,000 mg/m2 i.v. infused over 24 hours and MP 1,000 mg/m2 i.v. infused over 6 hours; regimen B, low-dose repetitive MTX 30 mg/m2 orally every 6 hours for six doses and i.v. MP; or regimen C, i.v. MTX alone. Intensification was given every 2 weeks for 12 courses. CNS prophylaxis was age-adjusted intrathecal MTX (ITM). In August 1992, the CNS prophylaxis was changed to age-adjusted triple intrathecal therapy (TIT). Reports of grades 3 and 4 acute NT were reviewed. RESULTS: Acute NT was reported in 95 of 1,218 (7.8%) eligible patients treated on POG 9005. The incidence by regimen was regimen A, 46 of 543 patients (8.3%); regimen B, 13 of 354 patients (3.7%); and regimen C, 36 of 321 patients (11.2%) (P < .001). The majority of events were seizures and the median number of days to first occurrence of symptomatic NT after ITM or TIT was 10 to 11 days. Computed tomography (CT) or magnetic resonance imaging (MRI) evidence consistent with leukoencephalopathy (LE), with or without the presence of cerebral calcifications, was observed in 75% and 77.1 % of symptomatic patients treated on regimens A and C, respectively, but in only 15.4% of symptomatic patients treated on regimen B (P < .001). Factors associated with an increased incidence of NT included increased cumulative exposure with repeated i.v. MTX (regimens A and C v B), increased MTX-leucovorin (LCV) ratio (regimens A and C v B), and choice and timing of TIT therapy. The use of i.v. MP during intensification did not appear to contribute to these complications. The switch to TIT CNS prophylaxis was associated with an inferior overall 4-year continuous complete remission (CCR) (P=.031) when compared with ITM. CONCLUSION: Intensification with repeated i.v. MTX in the setting of low-dose LCV rescue was associated with a higher risk for acute NT and LE, especially in patients who received concomitant TIT. The long-term consequences for affected patients remain unknown.

E2A-PBX1 chimeric transcript status at end of consolidation is not predictive of treatment outcome in childhood acute lymphoblastic leukemias with a t(1;19)(q23;p13): a Pediatric Oncology Group study.

A t(1;19)(q23;p13) is detected cytogenetically in approximately 5% of childhood acute lymphoblastic leukemias (ALLs) and its presence has been associated with an increased risk of relapse in several previously-completed Pediatric Oncology Group (POG) clinical trials. The t(1;19) fuses E2A to PBX1 in more than 95% of cases and this molecular abnormality can be reliably identified by polymerase chain reaction (PCR)-mediated amplification of E2A-PBX1 chimeric mRNAs. We used a nested PCR assay, which reproducibly detected a 10(4)- to 10(5)-fold dilution of t(1;19)+ into t(1;19)- cells, to evaluate minimal residual disease (MRD) in 48 children with t(1;19)+ ALL enrolled in POG clinical trials for lower (POG 9005) and higher (POG 9006) risk ALL. Peripheral blood (PB) and bone marrow (BM) samples were collected prospectively at the end of consolidation (weeks 25 and 31 after end of induction) and the presence or absence of PCR-detectable MRD was correlated with clinical outcome. Overall, 41 of 148 (28%) samples were PCR+. Of the 65 time points with informative results from both PB and BM, PCR results were concordant for 51 pairs (10 PB+/BM+, 41 PB-/ BM-) and discordant for 14 (5 PB+/BM-, 9 PB-/BM+), indicating that assessment of only PB or only BM can inaccurately classify some PCR+ cases as PCR-. There were no significant differences in event-free survival between PCR+ and PCR- patients. We conclude that qualitative detection of MRD by amplification of E2A-PBX1 chimeric mRNAs at the end of consolidation was not significantly predictive of outcome for children treated on POG 9005/9006 and that such results should not be used to alter therapy for patients with t(1;19)+ ALL.

Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial.

PURPOSE: To determine whether early intensification with 12 courses of intravenous methotrexate and intravenous mercaptopurine (IVMTX/IVMP) is superior to 12 courses of repetitive, low-dose oral MTX with I.V. MP (LDMTX/IVMP) for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Seven hundred nine patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction. Patients were randomized to receive intensification with either IVMTX 1,000 mg/m2 plus IVMP 1,000 mg/m2 (regimen A) or LDMTX 30 mg/m2 every 6 hours for six doses with IVMP 1,000 mg/m2 (regimen B). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy (TIT) was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and TIT every 12 weeks for 2 years. RESULTS: Six hundred ninety-nine (99%) patients achieved remission. Three hundred forty-nine were assigned to regimen A and 350 to regimen B. The estimated 4-year continuous complete remission (CCR) rate for patients treated with regimen A is 80.3% (SE = 2.9%) and with regimen B is 75.9% (SE = 3.1%). By log-rank analysis, regimen A demonstrated superior CCR (P = .013). Transient neutropenia/thrombocytopenia, bacterial sepsis, neurotoxicity, stomatitis, and hospitalizations were more frequent among patients treated on regimen A. CONCLUSION: Intensification with IVMTX/IVMP is more effective than LDMTX/IVMP for prevention of relapse in children with B-precursor ALL at lower risk for relapse.

Therapeutic trial for infant acute lymphoblastic leukemia: the Pediatric Oncology Group experience (POG 8493).

PURPOSE: Despite improved event-free survival of older children with acute lymphocytic leukemia (ALL), infants <1 year of age continue to have a very poor prognosis. A new therapy designed specifically for infants with ALL was initiated. PATIENTS AND METHODS: From 1984 until 1990, 82 eligible infants <1 year of age were entered on a Pediatric Oncology Group (POG) protocol 8493 for infant ALL. Compared to older patients, infants at diagnosis had more overt CNS leukemia (26%), higher initial WBC count (56% >50,000/microl), and a higher likelihood of CD-10 (CALLA) negative lymphoblasts (55%). A translocation involving chromosome 11 at band q23 was detected in 27 of 64 cytogenetically informative cases. Treatment was based upon two institutional pilot studies utilizing chemotherapy doses based upon body weight. Important components included remission induction with cyclophosphamide (Ctx), vincristine (Vcr), cytosine arabinoside (Ara-C), and prednisone (Pred) (COAP); consolidation therapy with teniposide (VM-26) and Ara-C; and continuation therapy with alternating pulses of COAP with VM-26/Ara-C separated by a methotrexate (Mtx) and 6-mercaptopurine (6-MP) backbone plus CNS therapy consisting of standard triple intrathecal therapy (TIT) (Mtx/hydrocortisone/Ara-C), which avoided the use of radiotherapy in this population. RESULTS: Seventy-six infants achieved a complete remission (93%). Fifty patients have relapsed: 35 isolated marrow relapses, five isolated CNS relapses, eight combined marrow and CNS relapses, and two other relapses. Actuarial event-free survival was 28% (SE = 5%) at 4 years. Infants >274 days (9 months) at diagnosis had a better outcome than those <274 days. CONCLUSIONS: This study represents a modest outcome improvement in comparison to previous experience with ALL for infants treated on POG trials. More effective therapy is still needed for infants with ALL.

Idarubicin and cytosine arabinoside reinduction therapy for children with multiple recurrent or refractory acute lymphoblastic leukemia: a Pediatric Oncology Group study.

PURPOSE: This study was designed to determine the toxicity of and response to idarubicin and cytosine arabinoside in children and adolescents with acute lymphoblastic leukemia (ALL) who had refractory or recurrent bone marrow disease. PATIENTS AND METHODS: Patients <21 years of age with ALL in second or later bone marrow relapse or refractory to induction therapy were eligible. Some patients also had concurrent central nervous system (CNS) relapse. Therapy consisted of cytosine arabinoside, 1 g/m2/day given as a 6-h infusion, followed by bolus idarubicin, 5 mg/m2/day, both daily for 6 days. Children achieving remission received maintenance therapy with 3 days of etoposide, 100 mg/m2/day, followed by ifosfamide, 2.8 g/m2/day, alternating every 3 weeks with 3 days of cytosine arabinoside and idarubicin in the dosages described earlier. All courses of therapy were followed by granulocyte colony-stimulating factor (G-CSF). Removal from study to undergo bone marrow transplantation (BMT) was encouraged. RESULTS: Eighty-two patients were entered. There were 14 deaths (nine early), mostly from documented or presumed bacterial or fungal sepsis. Overall, 30 patients achieved complete remission (37%). These were mostly of brief duration--only one patient was still alive at 600+ days after BMT. CONCLUSIONS: Cytosine arabinoside and idarubicin showed moderate activity in heavily pretreated children with ALL.

Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group.

BACKGROUND: The value of autologous bone marrow transplantation in the treatment of children with acute myeloid leukemia (AML) is unknown. We compared autologous bone marrow transplantation with intensive consolidation chemotherapy as treatments for children with AML in first remission. METHODS: We induced remission with one course of daunorubicin, cytarabine, and thioguanine, followed by one course of high-dose cytarabine (3 g per square meter of body-surface area for six doses). Patients in remission after the second course of induction therapy were eligible for randomization. Between June 1988 and March 1993, 552 of 649 enrolled patients who could be evaluated (85 percent) entered remission. A total of 209 patients were not eligible for randomization; of the remaining 343 patients, 232 were randomly assigned to receive six courses of intensive chemotherapy (117 patients) or autologous transplantation (115 patients). Of the original 649 patients, 189, including 21 with Down's syndrome, were nonrandomly assigned to receive intensive chemotherapy. RESULTS: The rates of event-free survival and overall survival for the entire group at three years were 34 +/- 2.5 percent and 42 +/- 2.6 percent, respectively. For patients who were randomly assigned to one of the two treatment groups, the mean (+/- SE) rates of event-free survival three years after randomization were not significantly different in the two groups when examined by intention-to-treat analysis: 36 +/- 5.8 percent for the intensive-chemotherapy group as compared with 38 +/- 6.4 percent for the autologous-transplantation group; and the relative risk of treatment failure for the chemotherapy group as compared with the autologous-transplantation group was 0.81 (P = 0.20 by the log rank test; 95 percent confidence interval, 0.58 to 1.12). Overall survival at three years followed a similar pattern. There was a lower relapse rate (31 percent vs. 58 percent, P < 0.001) but a higher rate of treatment-related mortality (15 percent vs. 2.7 percent, P = 0.005) in the group treated with autologous transplantation than in the intensive-chemotherapy group. The event-free survival at three years for the nonrandomized intensive-chemotherapy group was 39 +/- 5.1 percent, and for a contemporaneous group of patients each of whom received a histocompatible bone marrow transplant from a sibling, it was 52 +/- 8.0 percent. CONCLUSIONS: Treatment of children with AML in first remission with either autologous bone marrow transplantation or intensive chemotherapy prolongs event-free survival equally.

Pancytopenia with chromosomal fragility: vitamin B12 deficiency.

PURPOSE: Pancytopenia in children may have many etiologies. Chromosomal abnormalities with pancytopenia is of particular concern because clonal abnormalities indicate a neoplastic process. We describe three children who had vitamin B12 deficiency and who displayed pancytopenia with multiple chromosomal breaks, rearrangements, and deletions consistent with chromosomal fragility. Severe vitamin B12 deficiency is rare in children and should be considered in the differential diagnosis of a child with pancytopenia, dyserythropoiesis, and multiple chromosomal abnormalities. PATIENTS AND METHODS: Three children displayed pancytopenia with dyserythropoiesis in the bone marrow. Routine cytogenetic analyses in all three patients were performed and chromosome breakage study was performed on the peripheral blood of one patient after vitamin B12 supplementation. RESULTS: All three patients had severe vitamin B12 deficiency. Spontaneous chromosomal fragility was seen in routine cytogenetic analyses in all three patients. Vitamin B12 supplementation resolved the pancytopenia in all three patients and spontaneous and diepoxybutane-induced breakage rates in chromosomes were well within normal rates after therapy in one patient. CONCLUSION: The presence of pancytopenia with cytogenetic abnormalities in a child is worrisome. However, careful interpretation of dyserythropoiesis and megaloblastic changes in bone marrow in the aforementioned clinical situation would result in the correct diagnosis of a disorder that is easily cured.

Therapy of refractory or recurrent childhood acute myeloid leukemia using amsacrine and etoposide with or without azacitidine: a Pediatric Oncology Group randomized phase II study.

PURPOSE: A randomized study compared the combination of amsacrine (100 mg/m2/d on days 1 to 5) and etoposide (200 mg/m2/d on days 1 to 3) with the same two agents plus azacitidine (250 mg/m2/d on days 4 to 50) for the therapy of induction-resistant or relapse childhood acute myeloid leukemia (AML). PATIENTS AND METHODS: One hundred sixty-seven assessable children with AML who either had failed to respond to primary induction therapy (group 1, n = 41) or had relapsed (group 2, n = 126) were randomized. RESULTS: Overall, there were 56 complete responses (34%; SE 4%). Among primary refractory patients (group 1), the complete response rate was higher with the three-drug regimen (18% vs 53%, P = .03). In the relapsed patients (group 2), there was no difference in complete response rates related to treatment (31% vs 35%, P = .3). There were 17 early deaths. The major toxicities for both regimens were myelosuppression and infection. CONCLUSION: The overall complete response rate of 34% in this patient population is indicative of effective antileukemic activity. For patients with relapsed leukemia, the addition of azacitidine to etoposide and amsacrine did not improve response. The suggested advantage of the three-drug regimen for induction failures warrants further investigation.

Treatment of essential thrombocythemia with anagrelide.

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by persistent elevation in platelet count. It is a rare disorder in children, and children who have symptoms require treatment. We report the successful use of anagrelide, with few toxic effects, in the treatment of three children with ET.

Repetitive low dose oral methotrexate and intravenous mercaptopurine treatment for patients with lower risk B-lineage acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study.

BACKGROUND: This trial evaluated the toxicity and preliminary efficacy of a repeated oral low dose (LD) methotrexate schedule with intravenous mercaptopurine infusions as intensification therapy for children with lower risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS. From December 1986 to January 1991, 96 children with newly diagnosed, lower risk ALL were enrolled. Vincristine, L-asparaginase, and prednisone were used for remission induction. Age-based methotrexate was administered intrathecally (IT) for central nervous system (CNS) prophylaxis. An outpatient-based intensification treatment included LD methotrexate 30 mg/M2 every 6 hours for 5 doses, followed by intravenous mercaptopurine 1000 mg/M2 for 6 hours every 2 weeks for 12 courses. Leucovorin rescue was administered 48 hours after methotrexate treatment was begun. Maintenance therapy included standard daily oral mercaptopurine, weekly intramuscular methotrexate, and IT methotrexate every 12 weeks, for 2 years. RESULTS: All patients had disease remission. Thirty-two patients relapsed; there were 17 isolated bone marrow relapses, 10 isolated CNS relapses, 2 isolated testicular relapses, 1 marrow plus CNS relapse, 1 marrow plus testicular relapse, and 1 CNS plus testicular relapse. Event free survival (EFS) at 4 years was 66% (standard error, 7%) by Kaplan-Meier analysis. Complications associated with LD methotrexate/mercaptopurine courses were few and resulted in hospital readmissions in 2.4% of courses. Two patients were unable to comply with the oral LD methotrexate schedule and received intravenous methotrexate. Three patients were unable to complete scheduled maintenance because of hepatic or hematopoietic dysfunction. CONCLUSIONS: Low dose methotrexate/mercaptopurine can be administered safely on an outpatient basis to children with lower risk B-lineage ALL. However, there was a higher than expected incidence of bone marrow and CNS relapse. The reasons for this outcome were not completely clear but raise the possibility that LD methotrexate therapy may be less effective in preventing relapse than are higher dose, parenteral methotrexate regimens.

Diastolic runoff with widened arterial pulse pressure in an adolescent with widely metastatic testicular choriocarcinoma.

Widened arterial pulse pressure is often found with conditions having exaggerated diastolic runoff flow, such as aortic insufficiency and arteriovenous malformation. We report a 17-year-old boy with metastatic testicular choriocarcinoma and a widened pulse pressure. Ultrasonography and Doppler analysis revealed significant runoff flow into multiple large hepatic metastases. After chemotherapy, there was diminution in his metastases, a narrowing of the pulse pressure, and no evidence of runoff flow in the liver. These cardiovascular findings have not been previously described in association with metastatic vascular malignancies.

Presenting characteristics of trisomy 8 as the primary cytogenetic abnormality associated with childhood acute lymphoblastic leukemia. A Pediatric Oncology Group (POG) Study (8600/8493).

Although trisomy 8 is the single most common numerical abnormality in acute myeloid leukemia (AML), relatively few cases with acute lymphoblastic leukemia (ALL) and trisomy 8 have been reported. We report the clinical and laboratory features of seven children with ALL and trisomy 8 as the sole cytogenetic abnormality and review nine similar cases from the literature. Among the children studied by the Pediatric Oncology Group (POG) with newly diagnosed ALL, only 0.3% had trisomy 8 as the sole abnormality. Four of our patients had T-cell ALL and three had early pre-B ALL. Presenting clinical features were typical for the respective immunophenotypes. Six of the seven children achieved complete remission. Our study suggest that trisomy 8 is an infrequent, recurring abnormality among children with ALL, which appears to be associated with a T-cell immunophenotype.

Trisomy 21 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study (8602).

Of 1,036 children with newly diagnosed non-T, non-B acute lymphoblastic leukemia (ALL) and a demonstrated cytogenetic abnormality treated on the frontline Pediatric Oncology Group (POG) therapeutic trial 8602, there were 33 patients with trisomy 21 as the sole abnormality. Of these 33, 14 had Down syndrome (DS). Although the non-DS (NDS) trisomy 21 cases tended to be older than the DS cases, there were no other significant differences in clinicobiologic features nor in treatment outcomes between the DS and NDS groups, nor between the entire trisomy 21 group and the other chromosome abnormality group. Among NDS patients with +21 and one additional abnormality, +X, +16, -20, and structural abnormalities involving 6q or 12p were common findings. Kaplan-Meier event-free survival (EFS) curves showed a 4-year EFS of 80% (SE, 12%) in NDS trisomy 21 cases, 71% (SE, 22%) in DS cases with trisomy 21 as the sole abnormality, and 69% (SE, 2%) in cases with other chromosome abnormalities. Trisomy 21 as a sole acquired abnormality in NDS patients suggests a good prognosis.

Predictability of the t(1;19)(q23;p13) from surface antigen phenotype: implications for screening cases of childhood acute lymphoblastic leukemia for molecular analysis: a Pediatric Oncology Group study.

The t(1;19)(q23;p13) translocation occurs in approximately 5% of B-precursor acute lymphoblastic leukemias (ALLs) occurring in children. Its presence has been associated with a poor prognosis, which may be overcome with more intensive therapy. Although leukemic cells from cases of t(1;19)-ALL frequently express cytoplasmic mu heavy chains, their complete antigenic profile remains undefined. Among 697 consecutive cases of B-precursor ALL with complete phenotypic studies using a panel of monoclonal antibodies, 22 cases were found to carry the t(1;19). Twenty of 22 cases had an identical, complex phenotype characterized by homogeneous expression of CD19, CD10, and CD9; complete absence of CD34; and at least partial absence of CD20. Overall, this phenotype was seen in only 8.0% (56 of 697) of childhood B-precursor ALL. One of the two remaining t(1;19)-carrying cases conformed to this phenotype, but was lacking data for CD9. The other case differed by virtue of expression of CD34 and was also hyperdiploid with 55 chromosomes. Molecular studies showed E2A-PBX1 abnormalities in all examined cases (12 of 12) with the t(1;19), including the case lacking CD9 data. In contrast, no E2A-PBX1 abnormalities were detected in the sole t(1;19)-ALL with CD34 expression. Seventeen cases with the characteristic phenotype and uninformative cytogenetics were also molecularly analyzed and 5 of 17 (including 4 of 8 with unsatisfactory cytogenetics and 1 of 9 with a normal karyotype) contained E2A gene rearrangements and E2A-PBX1 fusion mRNAs. Our results show that all cases of t(1;19)-ALL with concomitant E2A-PBX1 fusion invariably express a characteristic but uncommon profile of surface antigens. These observations suggest that selective molecular analysis of a small subset of patients (those with uninformative cytogenetics and the characteristic phenotype) can identify a significant number of additional cases of ALL with E2A-PBX1 fusion that might benefit from more intensive therapy.