No prognostic effect of additional chromosomal abnormalities in children with acute lymphoblastic leukemia and 11q23 abnormalities.

This study characterized the additional chromosomal abnormalities (ACA) associated with 11q23 rearrangements in 450 infants and children with acute lymphoblastic leukemia (ALL) and examined the impact of these ACA on survival. Overall, 213 (47%) cases had ACA but the incidence varied according to patient age and 11q23 subgroup. Infants and patients with t(4;11)(q21;q23) had the lowest incidence of ACA (50/182 (27%) and 57/216 (26%) respectively), whereas patients with del(11)(q23) had the highest incidence (66/93 (71%)). Del(11)(q23) abnormalities were heterogeneous and occasionally secondary to t(9;22)(q34;q11.2). Thus, patients with del(11)(q23) comprised a separate biological entity, which was clearly distinct from those with an 11q23 translocation. The most frequent specific ACA were trisomy X (n = 38), abnormal 12p (n = 32), abnormal 9p (n = 28) and del(6q) (n = 19). The presence of ACA did not change the 5 year event-free survival estimates among children (56% (95% Cl 46-65%) vs 62% (54-69%)) or infants (22% (15-29%) vs 18% (9-29%)), nor when the different 11q23 subgroups were analyzed separately. This study has conclusively demonstrated that there is no prognostic effect of secondary chromosomal changes in association with 11q23 abnormalities in childhood ALL. However, characterization of these ACA is important to determine their potential role in initiation of MLL driven leukemogenesis.

Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia.

PURPOSE: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and l-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol. PATIENTS AND METHODS: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol. RESULTS: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate +/- SE was 69% +/- 7.0%, 83% +/- 4.4%, and 84% +/- 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P

Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

Long-term survival of children with leukemia achieved by the end of the second millennium.

BACKGROUND: The prognosis for patients with childhood leukemia has improved steadily over the last decades due to major progress in therapy. Much of this progress remains unaccounted for in traditional estimates of long-term survival rates, which essentially reflect the survival experience of patients who were diagnosed many years ago. METHODS: The authors applied a new method of survival analysis, called period analysis, to provide up-to-date estimates of long-term survival rates. The analysis is based on data from the nationwide German Childhood Cancer Registry and includes 8059 children who were diagnosed with leukemia between 1981 and 1998. The most up-to-date 5-year, 10-year, and 15-year survival estimates were obtained by period analysis and were compared with to the most up-to-date survival estimates from traditional methods of survival analysis. RESULTS: Period estimates (95% confidence intervals) of 5-year, 10-year, and 15-year survival rates achieved by 1998 were 81% (79-83%), 77% (74-79%), and 73% (70-76%), respectively, for all patients with leukemia combined; 86% (84-88%), 81% (79-84%), and 77% (74-81%), respectively, for patients with acute lymphocytic leukemia; and 59% (53-65%), 59% (53-65%), and 57% (49-64%), respectively, for patients with acute nonlymphocytic leukemia. Substantially lower estimates would have been obtained with traditional methods of survival analysis. CONCLUSIONS: These results from one of the world's largest childhood cancer registries reveal that cure rates of childhood leukemia achieved by the end of the second millennium are higher than suggested by previous estimates based on traditional methods of survival analysis.

[Minimal residual disease analysis in acute lymphoblastic leukemia of childhood within the framework of COALL Study: results of an induction therapy without asparaginase]. / Minimal Residual Disease Untersuchungen bei der akuten lymphatischen Leukämie im Kindesalter im Rahmen der COALL-Studie: Ergebnisse einer Induktionstherapie ohne Asparaginase.

UNLABELLED: The detection of minimal residual disease (MRD) is a major prognostic factor for treatment in acute lymphoblastic leukemia (ALL) of childhood. Several groups showed the predictive value of MRD after 5 weeks of chemotherapy (at the end of induction therapy). Patients with more than 1 leukemic cells in 100 cells (> or = 10(-2)) at this time-point have a significantly higher relapse rate. The MRD measurement has been shown to be an independent prognostic factor at several time points in the BFM study (ALL-BFM 90) as well as in the EORTC study. The aim of our investigations was the detection of MRD at the end of induction therapy within the COALL studies which is different from the above studies. In the COALL studies, therapy starts with a 1 week DNR prephase (24 h infusion on day one) and i.th. MTX. Induction therapy consisted of 3 drugs over a period of 4 weeks (Prednisolone, Vincristine and Daunorubicin), asparaginase is given later in consolidation. At the end of induction therapy, bone marrow was obtained for cytomorphologic and molecular analysis. PATIENTS AND METHODS: We investigated bone marrow samples from 76 patients. All patients were in morphologic remission at the end. of induction therapy. For MRD analysis, DNA was isolated from bone marrow mononuclear cells. Clonal T-cell-receptor (TCR) or immunoglobulin gene (IgH) rearrangements were identified by PCR. Monoclonal products were either sequenced directly (TCR) or after excision from high resolution agarose gels. Subsequently patient-specific oligonucleotides for allele-specific PCR were generated. PCR analysis was performed with 1 microgram DNA for each reaction within a semiquantitative matter. This method reached sensitivities down to 10(-5). RESULTS: Eighty-four percent of the analysed samples were MRD positive at the end of induction therapy. 20 out of 76 patient samples (26%) were highly positive (> or = 10(-2)), 28 patients had levels of about 10(-3) (37%), 16 had levels around 10(-4) (21%) and 12 patients had no detectable residual cells (16%). All analysed 15 T-ALL patients had detectable residual disease at this timepoint. Until now, 5/20 patients with very high MRD level at the end of induction therapy suffered a relapse. DISCUSSION: Patients with very high MRD level at the end of induction therapy showed an elevated risk of relapse, but the predictive value is much poorer than for example in the BFM 90 MRD-study. We suggest, that a high MRD level at this timepoint results from a different induction therapy compared to the BFM 90 study. In the COALL studies asparaginase is given only after induction therapy to decrease the risk of thrombosis. We would like to conclude that this differences were compensated later during therapy as the event free survival of both studies is similar. In conclusion, an optimal information from MRD studies is strongly associated with the given therapy. Therefore we initiated an additional MRD time-point after the first chemotherapy block in consolidation.

Co-operative study group for childhood acute lymphoblastic leukemia (COALL): long-term follow-up of trials 82, 85, 89 and 92.

The German Co-operative Study Group COALL for treatment of acute lymphoblastic leukemia (ALL) in childhood started the first trial in 1980. This report gives an overview of the long-term results of the four consecutive studies COALL-82, COALL-85, COALL-89 and COALL-92. Besides improvement in long-term survival major objectives were reduction of treatment-related toxicity by transferring asparaginase (ASP) from induction therapy to intensive phase and omitting CNS irradiation by stepwise increase of the initial white blood count (WBC) up to 50 x 10(9)/l (exception T-ALL) as criterion for irradiation. In study COALL-85 in high risk patients slow vs rapid rotational treatment was randomized. In study COALL-92 initial response to daunorubicin (DNR) as a 1-h vs 24-h infusion and its prognostic value was investigated. Furthermore, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were randomized in maintenance treatment. In total, 1191 eligible patients were enrolled. Induction treatment without ASP has been shown to be as effective and less hazardous than the former four-drug induction. CNS control could be obtained in most without cranial irradiation (CNS relapse-free survival >95%). The leukemic cell kill with a 24-h DNR infusion was equivalent to that of a 1-h infusion. DNR response was of less prognostic significance than prednisone response. The rapid rotation regimen failed to improve outcome as well as 6-TG in maintenance treatment. However, intensification of systemic treatment resulted in an increase in overall event-free survival (EFS) to approximately 80% which is comparable to other groups.

[In vitro drug resistance as independent prognostic factor in the study COALL-O5-92 Treatment of childhood acute lymphoblastic leukemia; two-tiered classification of treatments based on accepted risk criteria and drug sensitivity profiles in study COALL-06-97]. / Die In-vitro-Zytostatika-Resistenz als unabhängiger prognostischer Faktor in Studie COALL-05-92 zur Behandlung der akuten lymphoblastischen Leukämie im Kindesalter: Basis für eine Doppelstratifizierung nach traditionellen Risikokriterien und Resistenzprofil in Studie COALL-06-97. COALL Studiengruppe.

BACKGROUND: Risk-adapted therapy in acute lymphoblastic leukemia (ALL) of childhood relies on traditional risk factors such as age, white blood count, immunological subtype, chromosomal aberrations and response to treatment. In spite of risk-adapted therapy, however, 20-30% of the patients suffer a relapse and may have profited from more intensive therapy. On the other hand a third of the patients is probably overtreated considering cure rates of 30% with less intensive therapies in the seventies. Additional prognostic criteria are therefore urgently needed. In a retrospective Dutch study in childhood ALL drug sensitivity testing with the MTT assay was identified as a new highly significant prognostic factor. PATIENTS AND METHODS: In study COALL-92 in 140 patients in vitro drug sensitivity was performed on initial bone marrow or blood samples and as in the Dutch study a score was derived from the sensitivity of the 3 drugs prednisolone, vincristine and asparaginase (PVA score). For each drug a score of 1 (highest) to 3 (lowest sensitivity) is given. A score of 3 therefore indicates the best, a score of 9 the worst sensitivity. RESULTS: Probability of event-free survival (pEFS) according to the PVA score was 0.94 for score 3 + 4, 0.80 for score 5-7, 0.35 for Score 8 + 9 (0.47 for score 7-9). For analysis within the low risk (LR) group (age 1-10 years, WBC < 25/nl, common or pre-B-ALL, remission day 28, no translocation 9;22 or 4;11) and high risk (HR) group 252 patients of the Dutch study and the COALL study were combined. In the LR group pEFS was 1.00 for score 3 + 4, 0.76 for score 5-7, 0.38 for score 8 + 9 (0.54 for score 7-9); in the HR group pEFS was 0.91 for score 3 + 4, 0.69 for score 5-7, 0.45 for score 8 + 9 (0.56 for score 7-9). Multivariate analysis identified the PVA score as independent prognostic factor. NEW STUDY COALL-97: In the new study COALL-97 patients are first stratified according to HR and LR criteria and then are stratified again according to the PVA score. LR and HR patients with a score of 3 + 4 receive less intensive treatment in reinduction therapy to reduce the cumulative dose of anthracyclines and to mitigate the high rate of infectious complications during this part of the protocol. LR patients with a score of 7-9 are treated according to the HR protocol; HR patients with a score of 8 + 9 receive BMT if an HLA identical family donor is available. In study COALL-97 the results of the minimal residual disease study and day 15 bone marrow will be compared with the PVA score. CONCLUSIONS: In vitro drug sensitivity testing is an independent prognostic factor which allows adjustment of therapy to the individual risk of relapse in addition to the traditional risk factors. It can be assumed that in patients with a favourable resistance profile therapy can be reduced without loss of efficacy and that patients with an unfavourable resistance profile might profit from more intensive therapy.

A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies.

During T cell selection in the thymic cortex more than 90% of the thymocytes are eliminated by apoptosis. Based on this biology, we propose to define blasts of T cell acute lymphoblastic leukemia (ALL) with the phenotype of cortical thymocytes (CD1+ and/or CD4+ 8+) as selection-related (SR) and all other T-ALL immunophenotypes as non-selection-related (NSR). The COALL cooperative treatment studies for childhood ALL offer a tool to study the outcome in T-ALL subgroups as children with T-ALL are allocated uniformly to the high risk arm of the protocol. In the COALL-85, -89 and -92 protocols, 39/83 cases presented as SR and 44/83 cases as NSR. Five-year event-free survival of SR phenotype is significantly better compared to the NSR group (0.87 +/- 0.06 vs 0.66 +/- 0.07, log rank test, P = 0.01). T-ALL with SR phenotype is a distinct subgroup of leukemia with excellent prognosis under a high risk treatment protocol.

Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine.

Mercaptopurine (6MP) has been the standard drug for maintenance therapy of acute lymphoblastic leukemia. In a multicenter study we investigated whether thioguanine (6TG), which is converted more directly to the cytotoxic thioguanine nucleotides (TGN), offers a therapeutic advantage over 6MP. In this study (COALL-92), 6TG was randomized versus 6MP in maintenance therapy, whereby the doses of both drugs had to be adjusted to a white blood cell (WBC) count of between 2 and 3/nl. In 19 children the plasma levels of both drugs and/or the accumulation of their metabolites in red blood cells (RBC) were measured during intensive treatment in two consecutive chemotherapy blocks, and in 54 children the metabolites in RBC were measured every 3 months during daily treatment in maintenance therapy. There was a marked interindividual difference in the plasma kinetics of the two drugs; after identical doses of 100 mg/m2 an about 4-fold higher peak concentration of the parent drug was reached with 6MP. The main metabolites of 6TG were thioguanine nucleotides (TGN), whereas during 6MP treatment, methylated thioinosine nucleotides (TIN) predominated in erythrocytes. In patients receiving 6TG during maintenance therapy (22 patients) the concentration of methylated TGN reached about 40% of that of unmethylated TGN; after 6MP administration (32 patients) the methylated TIN were concentrated about 26-fold higher in RBC than were TGN. In contrast to 6TG, for 6MP the pattern of metabolites shifted toward the methylated ones with increasing dose. The median TGN concentration was about 7-fold higher in the TG branch, although the median dose was only about 70% of that of 6MP. The WBC values were equivalent in the two treatment groups. Our results suggest that the cytotoxic effect of 6MP is not based solely on the formation of TGN.