Smoking quit success genotype score predicts quit success and distinct patterns of developmental involvement with common addictive substances.

Genotype scores that predict relevant clinical outcomes may detect other disease features and help direct prevention efforts. We report data that validate a previously established v1.0 smoking cessation quit success genotype score and describe striking differences in the score in individuals who display differing developmental trajectories of use of common addictive substances. In a cessation study, v1.0 genotype scores predicted ability to quit with P=0.00056 and area under receiver-operating characteristic curve 0.66. About 43% vs 13% quit in the upper vs lower genotype score terciles. Latent class growth analyses of a developmentally assessed sample identified three latent classes based on substance use. Higher v1.0 scores were associated with (a) higher probabilities of participant membership in a latent class that displayed low use of common addictive substances during adolescence (P=0.0004) and (b) lower probabilities of membership in a class that reported escalating use (P=0.001). These results indicate that: (a) we have identified genetic predictors of smoking cessation success, (b) genetic influences on quit success overlap with those that influence the rate at which addictive substance use is taken up during adolescence and (c) individuals at genetic risk for both escalating use of addictive substances and poor abilities to quit may provide especially urgent focus for prevention efforts.

The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.

The recurrent translocation t(8;16)(p11;p13) is a cytogenetic hallmark for the M4/M5 subtype of acute myeloid leukaemia. Here we identify the breakpoint-associated genes. Positional cloning on chromosome 16 implicates the CREB-binding protein (CBP), a transcriptional adaptor/coactivator protein. At the chromosome 8 breakpoint we identify a novel gene, MOZ, which encodes a 2,004-amino-acid protein characterized by two C4HC3 zinc fingers and a single C2HC zinc finger in conjunction with a putative acetyltransferase signature. In-frame MOZ-CBP fusion transcripts combine the MOZ finger motifs and putative acetyltransferase domain with a largely intact CBP. We suggest that MOZ may represent a chromatin-associated acetyltransferase, and raise the possibility that a dominant MOZ-CBP fusion protein could mediate leukaemogenesis via aberrant chromatin acetylation.

Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma.

BACKGROUND: Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients. PATIENTS AND METHODS: This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered. RESULTS: There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths. CONCLUSIONS: MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.

Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN.

Caspase 8 is a cysteine protease regulated in both a death-receptor-dependent and -independent manner during apoptosis. Here, we report that the gene for caspase 8 is frequently inactivated in neuroblastoma, a childhood tumor of the peripheral nervous system. The gene is silenced through DNA methylation as well as through gene deletion. Complete inactivation of CASP8 occurred almost exclusively in neuroblastomas with amplification of the oncogene MYCN. Caspase 8-null neuroblastoma cells were resistant to death receptor- and doxorubicin-mediated apoptosis, deficits that were corrected by programmed expression of the enzyme. Thus, caspase 8 acts as a tumor suppressor in neuroblastomas with amplification of MYCN.

Pathogenesis of an infectious mononucleosis-like disease induced by a murine gamma-herpesvirus: role for a viral superantigen?

The murine gamma-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62L(lo)) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2(b)) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vbeta4+ phenotype. Interestingly, the Vbeta4 dominance was also seen, to varying extents, in H-2(k), H-2(d), H-2(u), and H-2(q) strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vbeta4 bias of the T cells, the Vbeta4+CD8+ expansion was absent in H-2IA(b)-deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody-depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vbeta4+CD8+ T cells.

Stroma-supported culture in childhood B-lineage acute lymphoblastic leukemia cells predicts treatment outcome.

We developed a stroma cell culture system that suppresses apoptosis of malignant cells from cases of B-lineage acute lymphoblastic leukemia. By multiparameter flow cytometric measurements of cell recovery after culture on stromal layers, we assessed the growth potential of 70 cases of newly diagnosed B-lineage acute lymphoblastic leukemia and related the findings of treatment outcome in a single program of chemotherapy. The numbers of leukemic cells recovered after 7 d of culture ranged from < 1 to 292% (median, 91%). The basis of poor cell recoveries from stromal layers appeared to be a propensity of the lymphoblasts to undergo apoptosis. The probability of event-free survival at 4 yr of follow-up was 50 +/- 9% (SE) among patients with higher cell recoveries ( > 91%), and 94 +/- 6% among those with reduced cell recoveries (+/- 91%; P = 0.0003). The prognostic value of leukemic cell recovery after culture exceeded estimates for all other recognized high-risk features and remained the most significant after adjustment with all competing covariates. Thus, the survival ability of leukemic cells on bone marrow-derived stromal layers reflects aggressiveness of the disease and is a powerful, independent predictor of treatment outcome in children with B-lineage acute lymphoblastic leukemia.

Clonal analysis of childhood acute lymphoblastic leukemia with "cytogenetically independent" cell populations.

Acute lymphoblastic leukemia (ALL) is generally regarded as a clonal disease in which a single abnormal progenitor cell gives rise to neoplastic progeny. Five of 463 cases of childhood ALL with adequately banded leukemic cells were found to have two cytogenetically independent cell populations. In addition, two of the four cases tested had more than two rearranged immunoglobulin genes and (or) T cell receptor genes. To investigate the clonality of these unusual leukemias, we examined the neoplastic cells for X-linked markers extrinsic to the disease. Leukemic cells from each of the three patients heterozygous for an X-linked, restriction fragment length polymorphism showed a single active parental allele, suggesting that both apparently independent cell populations developed from a common progenitor. These cases provide evidence that leukemogenesis involves a multistep process of mutation and suggest that karyotypic abnormalities may be a late event of malignant transformation.

Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridization.

We analyzed 27 samples of primary medulloblastoma, using comparative genomic hybridization and a novel statistical approach to evaluate chromosomal regions for significant gain or loss of genomic DNA. An array of nonrandom changes was found in most samples. Two discrete regions of high-level DNA amplification of chromosome bands 5p15.3 and 11q22.3 were observed in 3 of 27 tumors. Nonrandom genomic losses were most frequent in regions on chromosomes 10q (41% of samples), 11 (41%), 16q (37%), 17p (37%), and 8p (33%). Regions of DNA gain most often involved chromosomes 17q (48%) and 7 (44%). These findings suggest a greater degree of genomic imbalance in medulloblastoma than has been recognized previously and highlight chromosomal loci likely to contain oncogenes or tumor suppressor genes that may contribute to the molecular pathogenesis of this tumor.

In vitro cytotoxicity of docetaxel in childhood acute leukemias.

PURPOSE: In seeking to identify novel effective antileukemic agents, we assessed the in vitro activity of the taxoid docetaxel (Taxotere; Rhone-Poulenc Rorer, Antony, France) in primary leukemic cells supported in culture by bone marrow-derived stromal layers. MATERIALS AND METHODS: Bone marrow samples from children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were cultured on allogeneic bone marrow-derived stromal layers and exposed to various concentrations of docetaxel. After 7 days of culture, the number of viable leukemic cells were counted by flow cytometry and compared with that in parallel cultures without drugs. RESULTS: In 20 samples tested (15 B-lineage ALL, one T-lineage ALL, and four AML), the median cytotoxicity was 78% after a 7-day culture in the presence of 100 ng/mL docetaxel (range, 54% to 95%). The effects were dose-dependent and extended to all five ALL samples with the t(9;22)(q34;q11) (Philadelphia chromosome) or 11q23 abnormalities, karyotypes associated with an unfavorable outcome. Studies with continuously growing cell lines demonstrated that docetaxel exerted its cytotoxic effect by inducing apoptosis, and was consistently more effective than paclitaxel (Taxol; Bristol-Myers Squibb, Wallingford, CT) (mean 50% cell kill [LC50], 6.93 v 12.86 ng/mL in six leukemic cell lines). The antileukemic activities of docetaxel and vincristine were synergistic. While the mean (+/- SD) cytotoxicity of vincristine (0.1 ng/mL) was 11.2% +/- 7.3% and that of docetaxel (10 ng/mL) was 19.3% +/- 17.5% in CEM-C7 cells after 24 hours, combining the two agents increased the cytotoxicity to 62.5% +/- 20.7% (P = .003). CONCLUSION: Docetaxel, at concentrations achievable in vivo, is cytotoxic to ALL and AML cells. These results provide a rationale for clinical trials of docetaxel in patients with acute leukemia.

Early intensification of chemotherapy for childhood acute nonlymphoblastic leukemia: improved remission induction with a five-drug regimen including etoposide.

We tested the value of early intensification of chemotherapy in 68 consecutive children with acute nonlymphocytic leukemia (ANLL) who were admitted to St. Jude Children's Research Hospital from November 1983 through March 1987. Fifty-eight patients (85%) entered complete remission after treatment with etoposide (VP-16)/cytarabine (ara-C) (A), followed by daunorubicin (Dauno)/ara-C/thioguanine (6-TG) (B) and then VP-16/azacytidine (5-AZ) (C). Thirty percent of the complete responders, mainly those with an M4 or M5 leukemia subtype, attained M1 marrow status after component A, 60% after A + B, and 10% after A + B + C. Induction failures resulted primarily from absolute or relative drug resistance; there was only one death during this phase of therapy. Postremission treatment consisted of three pairs of drugs (vincristine [VCR]/amsacrine [m-AMSA], or doxorubicin [Doxo]/6-TG/ara-C, and VP-16/cyclophosphamide [CTX]) administered sequentially in 6-week cycles for 22 months. Despite the high rate of remission induction, only 33% +/- 7% SE of the patients are expected to be failure-free survivors at 2 years. Remission durations were not significantly affected by the majority of factors examined in this study, with the exception of marrow cellularity after VP-16/ara-C induction therapy. Patients with less than or equal to 5% leukemic cells survived relapse-free for a median of 36.1 months, compared with 11.3 months for the group with a larger infiltrate (P = .01). Although postremission therapy did not improve the percentage of long-term failure-free survivors, the induction regimen we used appears highly effective, and its components should be considered for inclusion in other treatment programs.

Secondary acute myeloid leukemia in children previously treated with alkylating agents, intercalating topoisomerase II inhibitors, and irradiation.

PURPOSE: Patient records were reviewed to identify cases of secondary acute myeloid leukemia (AML) with clinical and cytogenetic features characteristic of classic epipodophyllotoxin-related AML in patients whose prior treatment for cancer did not include these agents. PATIENTS AND METHODS: Four cases of secondary AML with chromosomal abnormalities involving bands 11q23 and 21q22, in the absence of prior treatment with etoposide or teniposide, were identified among patients treated at St Jude Children's Research Hospital between January 1980 and April 1992. RESULTS: The four identified patients were initially treated for rhabdomyosarcoma, non-Hodgkin's lymphoma (n = 2), and Hodgkins' disease. Prior chemotherapy included relatively low cumulative doses of doxorubicin (median, 150 mg/m2; range, 120 to 375 mg/m2) and cyclophosphamide (median, 3,100 mg/m2; range, 2,250 to 11,400 mg/m2). All four patients had received radiation therapy: 59.4 Gy to the right middle ear for rhabdomyosarcoma; 15 Gy and 12 Gy to the abdomen and right lower quadrant, respectively, for non-Hodgkin's lymphoma; 27 Gy to the right orbit for non-Hodgkin's lymphoma; and 36.6 Gy to the mantle-paraaortic-spleen regions plus 20.4 Gy inverted-Y radiation at relapse for Hodgkin's disease. Secondary AML was diagnosed a median of 38 months after initial diagnosis (range, 14 to 55). Leukemic cell translocations involved band 11q23 in two cases and band 21q22 in two. Although all patients obtained a complete remission (CR), only one remains disease-free (at 34 months), following an allogeneic bone marrow transplant. CONCLUSION: Intercalating topoisomerase II inhibitors (doxorubicin, dactinomycin), when combined with alkylating agents and irradiation, may cause secondary AML.

Intensive chemotherapy and low-dose radiotherapy for the treatment of advanced-stage Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study.

Sixty-two patients with advanced-stage Hodgkin's disease and a median age of 12 years (range, 3 to 22 years) were treated with four cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alternating with four cycles of doxorubicin, vinblastine, bleomycin, and dacarbazine (ABVD) followed by low-dose radiotherapy (RT). We determined the feasibility, immediate safety, and rapidity of response of patients to this regimen, as well as the relationship between prognostic factors and the rate of complete remission (CR), event-free survival (EFS), and overall survival. Therapy was well tolerated, and the major toxicity was hematopoietic. At the end of chemotherapy, 54 of 62 patients (87%) were in CR by clinical restaging, with a biopsy of residual disease where necessary. The actuarial 3-year EFS is 77% (SE, 11%), with a median follow-up of 35 months, and the survival is 91% (SE, 7%). With respect to EFS, female patients and those with stage II or III disease fared statistically better than males and patients with stage IV disease, respectively. Six patients have died: three of progressive Hodgkin's disease, one of secondary acute myelocytic leukemia (AML), one of secondary non-Hodgkin's lymphoma (NHL), and one of overwhelming bacterial sepsis. The Pediatric Oncology Group (POG) is currently engaged in a randomized study of these eight cycles of chemotherapy with and without RT to assess the role of RT in achieving comparable results.

Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19) (q23; p13) or its derivative.

PURPOSE: To evaluate the immunophenotypes, karyotypes, and clinical features, including treatment responses, of patients with childhood acute lymphoblastic leukemia (ALL) and either a t(1;19)(q23;p13) or a der(19)t(1;19)(q23;p13) translocation. PATIENTS AND METHODS: The lymphoblasts of 45 patients with a balanced translocation, t(1;19) or its derivative form, der(19)t(1;19), were analyzed by cytogenetic and immunologic methods for differences that might suggest distinct subtypes of ALL. This cohort was treated in four consecutive clinical trials with a median overall follow-up duration of 7 years. RESULTS: A pre-B immunophenotype was found in 10 cases with the balanced t(1;19) and 31 with the unbalanced der(19)t(1;19). The four remaining cases, each with a derivative t(1;19), were classified as early pre-B ALL. The characteristic surface antigen profile of the 41 pre-B cases was CD19+/CD10+/CD22+/CD34-/CD20+/-, whether the translocation was balanced or derivative. In contrast to the four early pre-B cases, which had hyperdiploid karyotypes (> 50 chromosomes), the pre-B cases were primarily pseudodiploid. Comparison of presenting clinical and laboratory features, as well as event-free survival, failed to disclose any differences that would warrant separation of pre-B cases with a balanced or derivative translocation. However, neither subgroup responded to therapy as well as patients with early pre-B ALL, each of whom remains in complete remission for > or = 3 years. CONCLUSION: The t(1;19) and the der(19)t(1;19) identify a relatively homogeneous group of patients with pre-B ALL, who can be expected to respond similarly to intensive chemotherapy. The exceptional cases have an early pre-B phenotype with hyperdiploid karyotypes and appear to have favorable prognosis.

Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study.

PURPOSE: To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C). RESULTS: The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A. CONCLUSION: We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).

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

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

Prognostic significance of CD34 expression in childhood B-precursor acute lymphocytic leukemia: a Pediatric Oncology Group study.

We studied the blasts from 795 children greater than 1 year of age with newly diagnosed, untreated B-precursor acute lymphoblastic leukemia (ALL) for expression of the hematopoietic stem cell-associated antigen CD34. All cases were confirmed as B-lineage lymphoblastic leukemia by virtue of expression of CD19 and/or CD22, lack of T-cell antigens, and lack of surface-membrane immunoglobulin (Ig). The CD34 antigen was present in at least 10% of blast cells in 587 (73.8%) of the patients. There was no significant difference in presenting clinical characteristics between CD34+ and CD34- patients save for an increased incidence of CNS involvement at diagnosis in the latter. Patients with CD34+ leukemia were more likely to have blasts expressing CD22, CD9, and CD13 antigens but were less likely to coexpress CD20. Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+. Although remission induction rates were not significantly different between patients with CD34+ and CD34-ALL (P = .23), event-free survival was shorter for patients with CD34- leukemia (P = .0014). Even though CD34 expression was associated with certain other known prognostically favorable variables including hyperdiploidy and lack of cytoplasmic Ig, it had an independent favorable effect on treatment outcome, even after adjusting for competing prognostic factors.

Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19).

In earlier studies of the cytogenetic characteristics of leukemic lymphoblasts from children with pre-B-cell acute lymphoblastic leukemia (ALL), we concluded that certain chromosomal abnormalities explain, in part, the increased presence of high-risk features at diagnosis and the less favorable response to therapy among patients with this immunologic subclass of ALL. With extended follow-up and a larger patient population, we have further evaluated the biologic and clinical aspects of pre-B leukemia. Of 686 cases of ALL with adequate immunophenotyping, 150 were classified as pre-B cell. Seventy-seven (69%) of the 112 pre-B cases with fully banded karyotypes had a translocation. The t(1;19) accounted for 28 (25%) of these pre-B cases and 31 (6.5%) of all 480 consecutively banded ALL cases. Three (2.6%) of the pre-B cases had a novel dicentric (7;9)(p1?3;p11) translocation. A t(9;22)(q34;q11) and a t(4;11)(q21;q23) were observed in seven (6%) and three (2.6%) of the cases, respectively. Within the pre-B subgroup, comparison of t(1;19) cases (n = 28) with those having other translocations (n = 49) or no identifiable translocations (n = 35) indicated that higher leukocyte counts (P = .002), absence of DNA indexes greater than 1.16 (P = .02), higher serum lactate dehydrogenase levels (P less than .0001), and a higher frequency of nonwhite race (P = .006) were significantly related to the t(1;19). Both the t(1;19) and other chromosomal translocations were associated with an adverse prognosis in the subset of patients treated from 1979 to 1984 (Total Therapy study X). In a more recent and more intensive chemotherapy program (Total Therapy study XI), neither the t(1;19) nor other chromosomal translocations has conferred an inferior outcome, suggesting that effective treatment can offset the negative impact of chromosomal rearrangements in cases of childhood pre-B ALL.

Prognostic importance of cytogenetic subgroups in de novo pediatric acute nonlymphocytic leukemia.

Reports of close associations between recurring chromosomal abnormalities and the clinical behavior of acute nonlymphocytic leukemia (ANLL) have stimulated efforts to define this disease in cytogenetic terms. Here we report on the leukemic cell karyotypes of 155 children with ANLL who were treated from 1980 to 1987 in consecutive programs of chemotherapy at this institution. Of 121 cases with adequate banding, 20% were normal, 30% had miscellaneous clonal abnormalities, and 50% were classified into known cytogenetic subgroups: inv(16)/del(16q) (n = 15), t(8; 21) (n = 14), t(15;17) (n = 9), t(9;11) (n = 9), t(11;V)/del(11q) (n = 7) and -7/del(7q) (n = 6). The inv(16)/del(16q) cases showed a nearly equal distribution of myelocytic and monocytic French-American-British (FAB) subtypes; only four of these patients presented with M4Eo morphology. Despite a 100% remission induction rate, patients with inv(16)/del(16q)-positive ANLL fared no better overall than the entire group; only 40% of this subgroup were event-free survivors at 2 years from diagnosis (P = .23). Patients with inv(16)/del(16q) frequently had CNS involvement at diagnosis (eight of 15) or initially relapsed in this site (three of eight). Event-free survival (EFS) was clearly superior for young patients with FAB M5 leukemia and the t(9;11) (P = .041). These patients were clinically indistinguishable from others with the FAB disease subtype, yet their responses to etoposide-containing therapies were noteworthy. By contrast, children with structural abnormalities involving 11q23, other than t(9;11), were infants (median age, 6 months) with FAB M4 or M5 leukemia, hyperleukocytosis, and frequent coagulation abnormalities. Patients with such changes [t(11;V) or del(11q)] relapsed early during postremission therapy: none remained disease-free more than 16 months from diagnosis. Because of resistant leukemia, patients with monosomy 7/del(7q) had a poor remission induction rate (17%; P = .0015); patients with the t(15;17) were also poor responders to induction therapy (44%; P = 0.02) because of hemorrhagic deaths. These results identify several cytogenetic subtypes of pediatric ANLL that may represent unique disease processes for which more effective early cytoreduction [-7/del(7q), t(11;V)], better supportive care measures [t(15;17)], or more effective CNS prophylaxis [inv(16)/del(16q)] would be warranted.

Immunophenotypes and karyotypes of leukemic cells in children with Down syndrome and acute lymphoblastic leukemia.

PURPOSE: Immunophenotypes and karyotypes of leukemic cells were analyzed in a large series of Down syndrome patients with acute lymphoblastic leukemia (ALL) to examine the frequency of adverse prognostic features in comparison with other patients with ALL. PATIENTS AND METHODS: Presenting features and leukemic cell characteristics were compared for 76 patients with Down syndrome and 4,733 other patients with newly diagnosed ALL treated on protocols of the Pediatric Oncology Group (POG) and St Jude Children's Research Hospital (SJCRH). Treatment outcome was analyzed for the patients with non-T-cell disease enrolled on a single trial, for whom adequate follow-up data were available. RESULTS: Down syndrome patients had lower platelet counts (P < .01) and were less likely to have an anterior mediastinal mass (P < .01) or CNS leukemia (P = .01). They were significantly more likely to have the pre-B immunophenotype (49% v 25.5%, P < .01) and less likely to have T-cell ALL (5.5% v 16%, P = .01). There was a notable absence among patients with Down syndrome of the t(4;11), t(1;19), and t(9;22), which are chromosomal translocations associated with an adverse prognosis in ALL. Treatment outcome did not differ significantly between patients with Down syndrome and the other children with non-T-cell ALL (P = .21); a third of the treatment failures in the former group resulted from treatment-related toxicities. CONCLUSION: Children with Down syndrome and ALL had a low frequency of adverse clinicobiologic features at diagnosis. However, these findings did not translate into a superior outcome, apparently because of treatment-related toxicity in this group. Future trials should focus on pharmacokinetics and other strategies to reduce toxicity in these compromised patients.

11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia.

PURPOSE: Leukemic cell characteristics were analyzed in infants less than 1 year of age with acute lymphoblastic leukemia (ALL) to determine adverse prognostic factors that might explain the poor prognosis of this group. PATIENTS AND METHODS: Treatment outcomes were analyzed according to the presenting clinical and laboratory features of 30 infants treated between May 1979 and April 1993. A stepwise multivariate regression model was used to identify the most important prognostic indicator with respect to event-free survival. RESULTS: Infant ALL cases were characterized by high presenting leukocyte count (median, 87 x 10(9)/L), increased frequency of CNS leukemia (50%), and blast cells with a CD10- phenotype (67%), myeloid-associated antigen expression (48%), and 11q23/MLL rearrangement (68%). The 11q23/MLL involvement was correlated with age less than 6 months, CD10- phenotype, myeloid-associated antigen expression, and high leukocyte count. Although 11q23/MLL involvement, age less than 6 months, myeloid-associated antigen expression, and female sex were each significantly associated with an inferior treatment outcome, only rearranged 11q23/MLL emerged as an independent predictor of prognosis in multivariate analysis (P = .01). Infants with this genetic abnormality had a 4.7-fold (95% confidence interval, 1.3- to 17.0-fold) increased risk in adverse events compared to other infants. CONCLUSION: The 11q23/MLL involvement of blast cells identifies a major subgroup of infant ALL cases that require an innovative treatment approach. Infants who lack this genetic abnormality have an intermediate prognosis and could be treated accordingly on risk-directed protocols.