Children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) have a poor prognosis, and there is no consensus on the optimal treatment for this variant of ALL.We reviewed the medical records of patients with Ph-positive ALL who were treated with intensive chemotherapy, with or without bone marrow transplantation, by 10 study groups or large single institutions from 1986 to 1996. Data on 326 children and young adults, who ranged in age from 0.4 to 19.9 years (median, 8.1), were analyzed to determine the rate of complete remission and the probability of event-free, disease-free and overall survival according to standard prognostic factors and type of treatment.The 267 patients who achieved a complete remission after induction chemotherapy (82 percent) were stratified into three subgroups according to the age and leukocyte count at the time of diagnosis: those with the best prognosis (a leukocyte count of less than 50,000 per cubic millimeter and an age of less than 10 years; 95 patients); those with an intermediate prognosis (intermediate-risk features; 92 patients); and those with the worst prognosis (a leukocyte count of more than 100,000 per cubic millimeter; 80 patients). The estimates of disease-free survival at five years (+/-SE) were 49+/-5 percent) for patients with the best prognosis), 30+/-5 percent (for those with an intermediate prognosis), and 20+/-5 percent (for those with the worst prognosis) (P<0.001 for the overall comparison). We also found that transplantation of bone marrow from an HLA-matched related donor offered significantly greater benefit than intensive chemotherapy alone in terms of protecting patients from relapse or other adverse events (relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001). This finding was consistent in all three groups.Unlike the usual type of all, Ph-positive ALL is associated with a poor prognosis. Nevertheless, in some patients with favorable prognosis features, the disease can be be controlled by intensive chemotherapy. Transplantation of bone marrow from an HLA-matched related donor is superior to other types of transplantation and to intensive chemotherapy alone in prolonging initial complete remissions.
The relationship between the prescribed dose of drugs during continuing (maintenance) therapy, the degree of marrow suppression caused, and subsequent event‐free survival was examined in a cohort of 740 children with lymphoblastic leukaemia treated on MRC UKALL X. Girls, younger children, and patients who had received intensification treatment, were prescribed lower doses of mercaptopurine, became neutropenic more readily, and had more interruptions of treatment. Children who had one or more episodes of neutropenia with a count of < 0.5 × 10 9 /l had a better prognosis than those who never became neutropenic. We conclude that early intensification treatment influences the probability of neutropenia during continuing treatment and that patients exhibiting myelosuppression during this phase of treatment have a better chance of prolonged remission.
Abstract Background Burkitt's lymphoma (BL) is a small non‐cleaved cell lymphoma which commonly presents as jaw swellings. Uncertainty remains as to the most effective form of management. Objectives To assess the evidence of any therapeutic strategy in the treatment of BL. Search strategy We searched MEDLINE (1966 ‐ March 2006), LILACS (1982 ‐ March 2006), EMBASE (1974 ‐ March 2006) and the Cochrane Controlled Trials Register (all years, latest Issue 01/2006) to identify relevant trials. All of these references were accessed in order to identify additional trials in BL. Selection criteria Randomised controlled trials (RCTs) of any duration were included. We included studies conducted in children with a confirmed diagnosis of BL. Studies were not restricted by geographical location or by language of publication. Any therapeutic intervention was considered. The primary outcome was overall survival. Data collection and analysis Two reviewers assessed studies for relevance. Studies that met the entry criteria were assessed for study quality. Data were extracted independently and were entered into RevMan 4.2. Main results Twelve studies met the entry criteria of the review but data could only be retrieved from ten. Inadequate reporting of study methodology was a common feature of the trials preventing thorough assessment of study quality. We were unable to pool data for any of the outcomes due to the differences between the interventions assessed in the studies. Seven studies aimed to induce remission: Overall survival did not differ significantly between treatment groups in three out of four studies reporting this outcome. Five studies aimed to maintain remission: In two out of three studies reporting survival, it was substantially, but not statistically significantly, different between treatment groups. Authors' conclusions This review does not currently provide any strong evidence on the relative effectiveness of interventions to treat Burkitt's lymphoma. The studies that have been conducted to date are small, underpowered and prone to both systematic and random error. Plain language summary Burkitt's lymphoma is an important cancer particularly in children. It is a fast growing tumour but also very sensitive to chemotherapy. Different regimens have been used to treat this condition with varied success rates. This review was to evaluate these treatments to assess their effectiveness in providing lasting cure. Data could only be reviewed for ten studies but results were difficult to collate due to study and reporting quality, with differing outcome measures, small trial sizes, and each addressing a different question. There is need for further research on treatment options.
The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry
Despite increasing emphasis on a more biological approach to treatment (Pinkel, 1996), there remains considerable interest in the problem of assigning prognosis in children with acute lymphoblastic leukaemia (ALL) (Chessells et al, 1995a, b), with the ultimate aim of giving risk-directed therapy. The Medical Research Council Working Party on Childhood Leukaemia in the United Kingdom has conducted a series of therapeutic trials for ALL (designated UKALL) which has involved >5000 children (Chessells et al, 1995a, b). In an analysis of the data from UKALL X and UKALL VIII combined (Chessells et al, 1995b), Cox regression was used to define a risk measure or ‘hazard score’ based on age, sex, and white cell count (WBC): where AGE = age in years; SEX = 1 if male, 2 if female, and where a hazard score 0.8 identified a group for whom the 5 years disease-free survival was <40%. These analyses have been repeated with longer follow-up. After these three risk factors, the next most significant factor was early response to treatment. Children having the common or pre-B ALL immunophenotype fared significantly better than other groups. Using the French–American–British (FAB) scheme for leukaemia morphological subtypes (L1, L2, L3), patients with L2 morphology had a worse prognosis. Children with B-ALL (L3 morphology) have been treated on a separate leukaemia/lymphoma protocol. The 15 Down's syndrome cases also fared worse, largely due to increased treatment-related mortality. Analysis of the cytogenetic variable ploidy (which describes the number of chromosomes) in 704 cases, indicated hyperdiploid ALL as favourable. The 13 children having the t(4;11) translocation had a worse prognosis, though this was not independently significant after allowance for age, because six were under 1 year and 2 over 10. Children with the cytogenetic Phl translocation also fared worse. A key question which remained unanswered by the Cox regression analysis was whether all the prognostic factors had been extracted from the trial database. A neural network is a powerful mathematical technique capable of determining association between inputs (in this case, prognostic factors) and outcomes (5-year survival), by systematic variation of parameters. Writing in the Lancet, Wyatt (1995) has suggested that a neural network analysis may be used to determine the maximum amount of prognostic information available in a database. From the original 1621 cases comprising the United Kingdom Medical Research Council UKALL X trial for childhood ALL, Down's syndrome patients, and those aged <1 year, were removed, as they are always classed as high risk. The remaining 1571 cases were used to develop (1271 cases, randomly selected) and compare (using the remaining 300 cases), the performance of two models which predicted survival at 5 years from diagnosis; the first was based on a Cox regression model, and the second model entailed an analysis based on a neural network analysis. A detailed account of model development is available from the authors. Receiver operating characteristic (ROC) (Chesters, 1992) curves express sensitivity against (1−specificity). The overall measure of predictive power is given by the proportion of the area lying under the curve, with 1 representing perfect predictive power and 0.5 equivalent to chance alone. The performance of both models was assessed by using ROC curves. The Cox regression model (COX) gave the risk score based classification rule: Death: if 0.0045(age)2− 0.4229sex + 0.2464 ln(white cell count +1) > C Otherwise: survival where, for C 1.8325, prediction is always survival (100% sensitivity and 0% specificity), and, for C −0.655, prediction is always non-survival (0% sensitivity and 100% specificity). The performance of the Cox approach was compared to that of the optimal neural network using age, sex and white cell count as inputs (NET1), and also against the best-performing network using any of the factors given above. The optimal overall network (NET2) was a weighted (2:1) combination of a three-input network (age, sex, white cell count) with a second ‘minor input’ net, utilizing the following variables; measures of liver and spleen size, presence of cervical and inguinal lymph nodes and cerebrospinal fluid involvement, cell type, FAB type and translocation scores. Based on 10 random assignments of the 1271/300 cases, and predicting overall 5-year survival from age, there was no significant difference (using Wilcoxon signed rank tests for pairwise comparison of differences of medians) between the two approaches in terms of mean ROC areas, and interpolated specificities for sensitivities of 75%, 60% and 45%. Table I shows the comparison of each neural network with the regression model. The limit on the accuracy of the predictive models was, in part, due to the presence of contradictory cases; that is, similar or identical clinical profiles resulting in different outcomes. It was concluded that, in the UKALL X dataset, factors predictive of outcome are fully described by a Cox regression analysis and that a neural network-based analysis identified no additional prognostic features. In this study the value of the network analysis lay in suggesting that the maximum amount of prognostic information has been extracted from the UKALL X database. This is clinically significant, in that the outcome for patients entered into UKALL studies is only partially determined by the factors present in the dataset. The future may lie in a more dynamic method of assessing prognosis by analysis of features at presentation in addition to response to therapy, and assessment of minimal residual disease during therapy (Evans et al, 1998). The financial support of The Leukaemia Research Fund (grant number 9653), The Leeds Children's Tumour Fund, and The Candlelighters Trust is gratefully acknowledged. This work was undertaken by St James's University Hospital which received funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the Executive.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)