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1.
Relapse is the major obstacle to cure for children with acute lymphoblastic leukaemia (ALL) after allogeneic bone marrow transplant (BMT). Development of salvage therapy for post-transplant relapse could be expedited by understanding the post-transplant behaviour of microscopically undetectable leukaemia and the ability to predict impending relapse. We have used a quantitative polymerase chain reaction method (sensitivity of 5.0 x 10-6) to measure residual leukaemia before the conditioning regimen, and at five time-points after transplantation. In total, 18 patients with ALL transplanted in first or second remission were studied for 1 year: For the first year post BMT, 12 remained in remission, four had haematological relapses, one had a cutaneous relapse, and one died of severe graft-versus-host disease. The post-engraftment levels of the leukaemia-specific immunoglobulin heavy (IgH) chain gene rearrangement for patients with haematological relapses were significantly different from those who remained in remission. The levels for the patients who remained in remission decreased with time, although there were occasional increases consistent with the known standard deviation of the measurement assay. In contrast, all clinical relapses were preceded by a rapid increase in levels. Both the rate of this increase and its timing were variable. These results suggest that residual leukaemia measurements can be used to direct post-transplant interventions and measure their effects.  相似文献   

2.
Minimal residual disease (MRD) diagnostics are used for risk group stratification in several acute lymphoblastic leukaemia (ALL) treatment protocols. It is, however, unclear whether MRD is homogeneously distributed within the bone marrow (BM) and whether this affects MRD diagnostics. We, therefore, analysed MRD levels in 141 paired BM samples (two independent punctures at different locations) from 26 ALL patients by real-time quantitative polymerase chain reaction (PCR) analysis of immunoglobulin and T-cell receptor gene rearrangements. MRD levels were comparable in 112 paired samples (79%), whereas two samples (both taken at day 15) had MRD levels that differed more than threefold. In the remaining 27 paired samples, MRD could be quantified or detected in one sample only. In four patients, MRD-based risk group classification was dependent on the site of BM puncture. Repetition of MRD analyses using 10-fold replicates instead of triplicates resolved most differences. In conclusion, MRD levels in paired BM samples were highly comparable, indicating that it is sufficient to analyse MRD in a single sample only. Nevertheless, MRD-based risk group classification can differ between paired BM samples, mainly because of variation below the quantitative range of the PCR assay rather than to a different distribution of leukaemic cells within the BM.  相似文献   

3.
4.
We report 12 years'experience with histocompatible, related donor marrow transplantation for 123 patients with acute lymphoblastic leukaemia; 104 second remission. Four regimens were studied: cyclophosphamide (Cy)+total body irradiation (TBI) ( n = 35); Cy + fractionated TBI ( n = 45); TBI + high-dose cytarabine ( n = 15); and hyperfractionated TBI + Cy ( n = 28). 45 patients survive (34 ± 9%: 95% confidence interval) between 1 and 12·7 years (median 7·8 years) following BMT and 29 ± 8% survive leukaemia-free. Significantly improved disease-free survival was observed in patients with an initial WBC < 50 x 109/l ( P = 0·02). Conditioning regimens tested yielded similar outcomes, though TBI/cytarabine led to greater treatment associated mortality. Leukaemia relapse was the most frequent cause of failure in 56 ± 11%; median time of relapse 8 months following BMT, none beyond 2·2 years. Relapse was more frequent with higher WBC, shorter initial remission and previous CNS leukaemia. Acute and/or chronic GVHD was associated with a strong trend ( P = 0·06) towards less relapse. Allogeneic BMT may be curative for a substantial fraction of patients with ALL, but additional anti-leukaemic measures beyond these conditioning modifications tested will be required to prevent post-transplant leukaemia recurrence.  相似文献   

5.
The influence of thiopurine methyltransferase (TPMT) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL2003, a trial in which treatment intensity was adjusted based on minimal residual disease (MRD). TPMT genotype was measured in 2387 patients (76% of trial entrants): 2190 were homozygous wild‐type, 189 were heterozygous for low activity TPMT alleles (166 TPMT*1/*3A, 19 TPMT*1/*3C, 3 TPMT*1/*2 and 1 TPMT*1/*9) and 8 were TPMT deficient. In contrast to the preceding trial ALL97, there was no difference in event‐free survival (EFS) between the TPMT genotypes. The 5‐year EFS for heterozygous TPMT*1/*3A patients was the same in both trials (88%), but for the homozygous wild‐type TPMT*1/*1 patients, EFS improved from 80% in ALL97% to 88% in ALL2003. Importantly, the unexplained worse outcome for heterozygous TPMT*1/*3C patients observed in ALL97 (5‐year EFS 53%) was not seen in ALL2003 (5‐year EFS 94%). In a multivariate Cox regression analysis the only significant factor affecting EFS was MRD status (hazard ratio for high‐risk MRD patients 4·22, 95% confidence interval 2·97–5·99, < 0·0001). In conclusion, refinements in risk stratification and treatment have reduced the influence of TPMT genotype on treatment outcome in a contemporary protocol.  相似文献   

6.
Intensive multi‐agent chemotherapy regimens and the introduction of risk‐stratified therapy have substantially improved cure rates for children with acute lymphoblastic leukaemia (ALL). Current risk allocation schemas are imperfect, as some children are classified as lower‐risk and treated with less intensive therapy relapse, while others deemed higher‐risk are probably over‐treated. Most cooperative groups previously used morphological clearance of blasts in blood and marrow during the initial phases of chemotherapy as a primary factor for risk group allocation; however, this has largely been replaced by the detection of minimal residual disease (MRD). Other than age and white blood cell count (WBC) at presentation, many clinical variables previously used for risk group allocation are no longer prognostic, as MRD and the presence of sentinel genetic lesions are more reliable at predicting outcome. Currently, a number of sentinel genetic lesions are used by most cooperative groups for risk stratification; however, in the near future patients will probably be risk‐stratified using genomic signatures and clustering algorithms, rather than individual genetic alterations. This review will describe the clinical, biological, and response‐based features known to predict relapse risk in childhood ALL, including those currently used and those likely to be used in the near future to risk‐stratify therapy.  相似文献   

7.
The remarkable progress in the treatment of childhood acute lymphoblastic leukaemia (ALL) has been based on the adjustment of therapy to subgroups of leukaemia stratified by their prognostic implications. Here, the contribution of the last decade of advanced genomic research on the clinical management of childhood ALL is examined. The application of genomics for routine diagnosis of ALL is feasible but depends on commercial development of appropriate certified platforms. The discovery of several novel high‐risk markers, such as deletions in IKZF1 might be integrated into clinical protocols in the near future. Several novel targets for therapy have been identified and have led to phase I/II therapeutic trials. This and any future progress depends on the maintenance of high quality bio‐banks including biological material and clinical data of each patient enrolled on a prospective clinical protocol.  相似文献   

8.
Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment‐related mortality of 8%. Leukaemia‐free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre‐HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre‐HSCT (LFS 41%, OS 64%, P < 0·0001) or post‐HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B‐other ALL had more relapses (CIR 50%, LFS 41%) than T‐ALL and the main precursor‐B subtypes including BCR‐ABL1, KMT2A (MLL), ETV6RUNX1 (TELAML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B‐other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post‐HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post‐HSCT therapy.  相似文献   

9.
10.
Four children with acute lymphoblastic leukaemia (ALL) who relapsed after allogeneic bone marrow transplantation (BMT) were treated with donor lymphocyte infusion (DLI) without prior conditioning. Three patients had previously received a non-T-cell-depleted matched sibling BMT and the fourth had a T-cell-depleted matched unrelated BMT. Two patients developed grade III–IV acute graft-versus-host-disease (GVHD) of the skin, which required intervention. Both are alive in complete haematological remission 7 and 10 months from DLI with chronic GVHD of the skin requiring immunosuppressive therapy. A third patient went into haematological remission 6 weeks after DLI, but with no clinical evidence of GVHD. His bone marrow remained in remission 11 months post-DLI despite the disease (ALL) relapsing in extramedullary sites. The fourth patient showed no clinical or haematological response to three consecutive doses of DLI given at 4-weekly intervals and died from progressive disease 11 months after relapse. These preliminary observations indicate that in constrast to experience in adult ALL, DLI may be effective in inducing sustained remission in children with ALL relapsing after BMT, and a response may occur even in the absence of clinical evidence of GVHD.  相似文献   

11.
Haematogones are normal, maturing B-cell precursors. They can be confused with neoplastic immature lymphoid cells of B lymphoblastic leukaemia/lymphoma or B-cell acute lymphoblastic leukaemia (B-ALL). Though multi-colour flow-cytometry strategies for distinguishing haematogones from cells of B-ALL are well-described, similar strategies have not been determined for bone marrow trephine biopsies (BMTB). We revisited the morphological and immunohistochemical features (CD20, CD34, TdT and PAX5 expression) in 69 BMTB from 62 patients - 27 with excess haematogones; seven with residual B-ALL after therapy; 18 with no reported excess of haematogones or residual acute leukaemia on BMTB; and 17 diagnostic samples of B-ALL. The distinctive immunophenotypic pattern of BMTB with excess haematogones was of CD34, TdT, CD20 and PAX5 accounting for increasing proportions of cells in the order mentioned, whereas among B-ALL, the immunohistochemical pattern was of CD20, PAX5 and TdT accounting for an equal proportion of cells. Furthermore, among haematogones, the intensity of CD20 expression was extremely heterogeneous as compared to the neoplastic cells in CD20-positive B-ALL. The TdT-positive haematogones were generally small and uniform, while a certain degree of heterogeneity was noticed among neoplastic B-ALL cells. This study provides a practical strategy to distinguish haematogones from B-ALL cells in BMTB.  相似文献   

12.
We report a largely retrospective analysis of minimal residual disease (MRD) in a cohort of 66 children suffering from acute lymphoblastic leukaemia (ALL). All patients lacked high-risk features at diagnosis, i.e. the presenting white cell count was <50 × 109/l, age 1–16 years and translocations t(9;22) and t(4;11) were not present. All were treated according to either the MRC protocols UKALL X or XI. PCR of IgH, TCRδ and TCRγ gene rearrangements and allele-specific oligoprobing were employed for the detection of MRD. Sensitivity was at least 10−4 in 78/82 (93%) probes examined.
A total of 33 patients relapsed (seven on therapy and 26 off) and 33 remain in continuing complete remission (CCR) (median follow-up 69 months from diagnosis). Of those who remain in CCR, MRD was present in the bone marrow in 32%, 10% and 0% at 1, 3 and 5 months into therapy respectively. This is in marked contrast to the presence of MRD at these times in 82%, 60% and 41% of patients who relapsed ( P <0.001, P <0.005 and P <0.005). These results provide further evidence of a strong correlation between clearance of MRD early in therapy and clinical outcome in childhood ALL.  相似文献   

13.
Analysis of differentiation antigens on leukaemic blasts is routinely done for diagnostic purposes, i.e. determination of stage of differentiation and lineage assignment. Acute lymphoblastic leukaemias are also frequently characterized by a leukaemia-associated immunophenotype (LAIP), either the coexpression of differentiation antigens physiologically restricted to other stages of differentiation (asynchronous LAIP) or cell lineages (aberrant LAIP). We defined LAIP in 241 consecutive unselected B-lineage (n = 193) and T-lineage (n = 48) ALL by three-colour flow cytometry using directly conjugated monoclonal antibodies. The incidence of LAIP was found to be 91.7%. In 63% of patients two to six leukaemia-associated expression patterns were detected. In order to study the specificity of LAIP in a therapy-relevant setting, remission bone marrow samples from patients with B-lineage ALL were analysed for the expression of T-lineage-associated phenotypes on the normal bone marrow cells and vice versa. The frequency of all T-lineage LAIP+ cells and all aberrant B-lineage LAIP+ cells was <1% in regenerating bone marrow samples at different timepoints. The incidence and clinical significance of LAIP+ cells was studied in 196 remission marrows of 70 ALL patients (55 remaining in CCR, 14 with bone marrow relapse, one with isolated CNS relapse). The presence of >1% LAIP+ at two consecutive timepoints predicted 5/8 bone marrow relapses in B-lineage ALL. The occurrence of LAIP+ cells >1% in T-lineage ALL after induction therapy predicted relapse in 7/7 cases. In conclusion, flow cytometric detection of LAIP+ cells appears to be a powerful tool for the prediction of outcome in ALL.  相似文献   

14.
The treatment of adults with Philadelphia-negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time to complete remission. In recent years, status of minimal residual disease (MRD) has been postulated as an additional risk criterion. This study prospectively evaluated the significance of MRD. Patients were treated with a uniform Polish Adult Leukemia Group (PALG) 4-2002 protocol. MRD status was assessed after induction and consolidation by multiparametric flow cytometry. Out of 132 patients included (age, 17–60 years), 116 patients were suitable for analysis. MRD level ≥0·1% of bone marrow cells after induction was found to be a strong and independent predictor for relapse in the whole study population ( P  < 0·0001), as well as in the standard risk (SR, P  = 0·0003) and high-risk ( P  = 0·008) groups. The impact of MRD after consolidation on outcome was not significant. The combination of MRD status with conventional risk stratification system identified a subgroup of patients allocated to the SR group with MRD <0·1% after induction who had a very low risk of relapse of 9% at 3 years as opposed to 71% in the remaining subjects ( P  = 0·001). We conclude that MRD evaluation after induction should be considered with conventional risk criteria for treatment decisions in adult ALL.  相似文献   

15.
Detection of minimal residual disease (MRD) after induction and consolidation therapy is highly predictive of outcome for childhood acute lymphoblastic leukaemia (ALL) and is used to identify patients at high risk of relapse in several current clinical trials. To evaluate the prognostic significance of MRD at other treatment phases, MRD was measured by real-time quantitative polymerase chain reaction on a selected group of 108 patients enrolled on the Australian and New Zealand Children's Cancer Study Group Study VII including 36 patients with a bone marrow or central nervous system relapse and 72 matched patients in first remission. MRD was prognostic of outcome at all five treatment phases tested: at day 15 (MRD ≥ 5 × 10−2, log rank P  < 0·0001), day 35 (≥1 × 10−2, P  = 0·0001), 4 months (≥5 × 10−4, P  < 0·0001), 12 months (MRD ≥ 1 × 10−4, P  = 0·006) and 24 months (MRD ≥ 1 × 10−4, P  < 0·0001). Day 15 was the best early MRD time-point to differentiate between patients with high, intermediate and low risk of relapse. MRD testing at 12 and particularly at 24 months, detected molecular relapses in some patients up to 6 months before clinical relapse. This raised the question of whether a strategy of late monitoring and salvage therapy will improve outcome.  相似文献   

16.
Minimal residual disease (MRD) has acquired a prominent role in the management of childhood and adult Acute Lymphoblastic Leukaemia (ALL) for its high prognostic value. Several studies have demonstrated the strong association between MRD and risk of relapse in childhood and adult ALL, irrespective of the methodology used. MRD is now used in clinical trials for risk assignment and to guide clinical management. Negativity at early time points may be considered to decrease treatment burden in patients who are likely to be cured with reduced intensity regimens. On the other hand, high MRD levels at late time points (end of consolidation) define ALL subgroups which deserve investigation of more effective treatments. The predictivity of MRD as a measurement of drug response in vivo opened new perspectives for its use in clinical decision, to deliver risk-based treatments, and possibly as a surrogate for efficacy in the evaluation of novel therapeutic approaches.  相似文献   

17.
The prognostic relevance of karyotype has been established in adult acute lymphoblastic leukaemia (ALL) patients treated with chemotherapy but not definitively evaluated in an allogeneic bone marrow transplantation (BMT) setting. To determine the factors affecting the outcome of allogeneic BMT for adults with precursor B-lineage ALL in first or second complete remission (CR), a total of 41 consecutive patients with a successful karyotype were enrolled in this study. There were 21 men and 20 women with a median age of 27 (15-43) years. The distribution of French-American-British (FAB) subtypes was as follows: L1 (n = 26), L2 (n = 15). Unfavourable karyotypes (n = 12) were defined as Ph+ or t(4;11). Disease status at the time of transplant was first CR (n = 35) or second CR (n = 6). With a median follow-up of 36 months, the 3-year probabilities of relapse and disease-free survival (DFS) were 36.3 +/- 8.4% and 57.3 +/- 8.4% respectively. Potential variables predicting worse relapse and DFS were FAB subtype (L2), extramedullary involvement, pre-BMT status (second CR), unfavourable karyotype and type of graft-versus-host disease (GVHD). Further multivariate analysis showed that karyotype and pre-BMT status were independently associated with relapse and DFS. In addition, chronic GVHD was found to be significantly associated with a lower relapse rate.  相似文献   

18.
The population-based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)-driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10−3 at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD ≥5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre-HCT MRD results, 22 were MRD-positive, one with MRD ≥10−3. After a median follow-up of 5·5 years, the cumulative incidence of relapse was 23·5% (95% confidence interval [CI]: 10·5–47·7) for MRD-positive versus 5·1% (95% CI: 1·3–19·2), P = 0·02) for MRD-negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9·1, 95% CI: 1·6–51·0, P = 0·012). Non-relapse mortality did not differ between the two groups, resulting in disease-free survival of 85·6% (95% CI: 75·4–97·2) and 67·4% (95% CI: 50·2–90·5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre-HCT MRD-positive patients.  相似文献   

19.
The predictive value of molecular minimal residual disease (MRD) monitoring using polymerase chain reaction amplification of clone-specific immunoglobulin or T-cell Receptor rearrangements was analysed in 161 patients with non T-lineage Philadelphia-negative acute lymphoblastic leukaemia (ALL) participating in the UK arm of the international ALL trial UKALL XII/Eastern Cooperative Oncology Group (ECOG) 2993. MRD positivity (≥10−4) in patients treated with chemotherapy alone was associated with significantly shorter relapse-free survival (RFS) at several time-points during the first year of therapy. MRD status best discriminated outcome after phase 2 induction, when the relative risk of relapse was 8·95 (2·85–28·09)-fold higher in MRD-positive (≥10−4) patients and the 5-year RFS 15% [95% confidence interval (CI) 0–40%] compared to 71% (56–85%) in MRD-negative (<10−4) patients ( P  = 0·0002) When MRD was detected prior to autologous stem cell transplantation (SCT), a significantly higher rate of treatment failure was observed [5-year RFS 25% (CI 0–55%) vs. 77% (95% CI 54–100%) in MRD-negative/<10−4, P  = 0·01] whereas in recipients of allogeneic-SCT in first complete remission, MRD positivity pre-transplant did not adversely affect outcome. These data provide a rationale for introducing MRD-based risk stratification in future studies for the delineation of those at significant risk of treatment failure in whom intensification of therapy should be evaluated.  相似文献   

20.
. Maintenance chemotherapy for up to 3 years is traditionally given to patients with acute lymphoblastic leukaemia (ALL) achieving complete remission. We questioned the value of such maintenance therapy in adult patients treated with intensive induction/consolidation. In a phase II study (SAKK 33/86) 63 patients between 17 and 72 years of age (median 27 years) with newly diagnosed ALL were treated with three intensive cycles of marrow-ablative chemotherapy. All subtypes were included. No maintenance phase was added. 53 patients (84%) entered a complete remission (CR) and 21 (33%) continue to be in unmaintained remission for 11-69 months (median 21 months). The disease-free survival of patients achieving CR and completing all three cycles is 40% at 3 years, with a 95% confidence interval of ± 19%. These findings are comparable to the results of conventional studies. We conclude that maintenance therapy might not be needed in all adult ALL patients. Its value should be tested in a randomized trial. For patients failing, novel approaches are needed to improve outcome in adult ALL.  相似文献   

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