Five-year survival is 92.5% (95% confidence interval [CI], 90%-94%) and eventfree survival (EFS) 91% (95% CI, 89%-93%). EFS is 98% (95% CI, 90%-100%), 92% (95% CI, 89%-95%), and 84% (95% CI, 77%-90%) for group A, B, and C, respectively. In group B, multivariate analysis of prognostic factors showed that a lactate dehydrogenase level more than 2-fold the normal value, no response after COP, and age of at least 15 years were associated with a lower EFS. CNS involvement was the only prognostic factor in group C. (Blood. 2001;97:3370-3379)

From April 1984 to December 1987, the French Pediatric Oncology Society (SFOP) organized a randomized trial for advanced-stage B-cell lymphoma without CNS involvement to study the possibility of reducing the length of treatment to 4 months. After receiving the same three intensive six-drug induction courses based on high-dose fractionated cyclophosphamide, high-dose methotrexate (HD MTX), and cytarabine in continuous infusion, patients were evaluated for remission. Those who achieved complete remission (CR) were randomized between a long arm (five additional courses with two additional drugs; 16 weeks of treatment) and a short arm (two additional courses; 5 weeks). For patients in partial remission (PR), intensification of treatment was indicated. Two hundred sixteen patients were registered: 15 stage II nasopharyngeal and extensive facial tumors, 167 stage III, and 34 stage IV, 20 of the latter having more than 25% blast cells in bone marrow. The primary sites of involvement were abdomen in 172, head and neck in 30, thorax in two, and other sites in 12. One hundred sixty-seven patients are alive in first CR with a minimum follow-up of 18 months; four are lost to follow-up. Eight patients died from initial treatment failure, 14 died from toxicity or deaths unrelated to tumor or treatment, and 27 relapsed. The event-free survival (EFS), with a median follow-up of 38 months, is 78% (SE 3) for all the patients, 73% (SE 11) for the stage II patients, 80% (SE 3) for the stage III patients, and 68% (SE 8) for the stage IV and acute lymphoblastic leukemia (ALL) patients. One hundred sixty-six patients were randomized: 82 in the short arm and 84 in the long arm. EFS is, respectively, 89% and 87%. Statistical analysis confirms equivalence of both treatment arms with regard to EFS. Moreover, morbidity was lower in the short arm. This study confirms the high survival rate obtained in the previous LMB 0281 study without radiotherapy or debulking surgery and demonstrates the effectiveness of short treatment.

Bcl-2 over-expression has been shown to inhibit apoptosis induced by a variety of stimuli, whereas a predominance of Baxa to Bcl-2 accelerates apoptosis upon apoptotic stimuli. We sought to study the relevance of these apoptotic regulating gene products in leukaemia. In a panel of leukaemia and lymphoma cell lines (HL60, DoHH2, CEM C7, L1210 and S49), the Baxa-to-Bcl-2 ratio as assessed by Western-blot analysis correlated with sensitivity to dexamethasone treatment. In addition, in HAbaxa-transfected CEM C7 clones, a similar correlation was found for dexamethasone and thapsigargin sensitivity. In bone-marrow aspirates from patients with childhood acute lymphoblastic or myelocytic leukaemia (ALL, n 5 48; AML, n 5 8), the Bcl-2 and Baxa levels were highly variable, but well within the range found in the Baxa transfectants and in the established cell lines. Bcl-2 levels were lower in T-than in B-lineage ALL, which could be ascribed to simultaneous inverse relation between Bcl-2 and WBC. By contrast, Baxa:Bcl-2 was independent of any presenting feature and was largely dependent on Baxa levels. Results suggest that Baxa:Bcl-2, rather than Bcl-2 alone is important for the survival of drug-induced apoptosis in leukemic cell lines and ALL. Int. J. Cancer 71:959-965, 1997.r 1997 Wiley-Liss, Inc.Bcl-2 was initially identified because of its involvement in the chromosomal translocation t(14;18), resulting in high levels of the 26-kDa Bcl-2 protein. Bcl-2 over-expression was subsequently shown to inhibit apoptosis (for review, see Reed, 1995). Moreover, over-expression of Bcl-2 has been implicated in the insensitivity of cells to a variety of anti-cancer drugs, especially those used in the chemotherapy of childhood ALL, notably glucocorticoids (GC) (Miyashita and Reed, 1992;Sentman et al., 1991;Smets et al., 1994). Bcl-2 may, therefore, define a new category of drugresistance genes regulating the physiological cell-death pathway (Reed, 1995). Accordingly, increased levels of Bcl-2 may be associated with poor prognosis in leukaemia by a dual action. First, it could expand the population of circulating blasts by promoting their survival and, second, it could antagonize response to chemotherapy by inhibiting steroid hormone-and cytostatic-drug-induced apoptosis. Attesting to this view, high expression of Bcl-2 has been associated with high WBC and poor prognosis in adult AML (Campos et al., 1993).In childhood ALL, the role of Bcl-2 is not clear yet. A number of studies (Campana et al., 1993;Gala et al., 1994;Coustan-Smith et al., 1996) agree that high Bcl-2 expression is the rule in ALL blasts, compared with their normal precursors, while no study found an association between Bcl-2 levels and the presenting features immunophenotype, ploidy and WBC. Increased expression of Bcl-2 was not found to correlate with prognosis in one study (Gala et al., 1994), but correlated with poor initial response to chemotherapy in another report (Maung et al., 1994). By contrast, CoustanSmith et al. (1996) found that elevated levels of Bcl-2 we...

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To determine whether the ALL (acute lymphoblastic leukemia) CDR3 (third complementarity-determining region) repertoire represents the recombination repertoire, or shows evidence of selectional processes inherent to normal B cell differentiation or malignant transformation, we analyzed 68 ALL CDR3 regions and included 127 previously published sequences in the analyses. We found no evidence of selection prior to malignant transformation as recombination was random with 1/3 "in frame" and 2/3 "out of frame" joinings and usage of all three D reading frames was observed. D and JH gene segments were predominantly unmutated which allowed a detailed analysis of gene usage and rearrangement characteristics. JH4 and JH6 usage (both 32.2%) was significantly different (p = 0.005) from that observed in peripheral B lymphocytes. D gene family usage roughly represented D gene family size with the exception of the DXP and DA/K family which were over- and underrepresented (p = < or = 0.05), respectively. D-D fusions were found in 26.2% of CDR3 regions. If less stringent criteria were applied DIR homology was found in 40/65 sequences, suggesting the frequent involvement of DIR gene segments in human CDR3 formation. The rearranged D genes were evenly distributed over the D locus, suggesting that D recombination is a predominantly random process, independent of physical location at the locus. Also, there was no correlation between JH gene usge and physical location of the rearranged D gene segment, which excludes a major contribution of the DJH replacement recombination mechanism. In 36.1% of CDR3 regions N-nucleotides at the DJH junction were absent. This frequency is higher than observed for peripheral B lymphocytes. It is suggested that for a number of ALL the initial transformational event took place in early fetal life. We conclude that ALL CDR3 sequences show no evidence of selection prior to malignant transformation, nor of extensive changes subsequent to malignant transformation.

Gonadal function of long term survivors of pediatric Hodgkin's disease treated with MOPP chemotherapy is severely impaired permanently.

Immunoglobulin heavy chain (IgH) oligoclonality in childhoodrearrangement occurs in each patient and that the type

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