Chimerism and minimal residual disease monitoring after reduced intensity conditioning (RIC) allogeneic transplantation.

Since graft-versus-leukemia (GVL) is the main weapon for disease eradication after reduced intensity conditioning (RIC) allogeneic SCT, the availability of sensitive and specific techniques to monitor changes in tumor load after transplant are especially helpful. These minimal residual disease techniques would allow an early intervention in the event of low tumor burden, for which immunotherapy is highly effective. Some authors have found an association between persistence of MRD, mixed chimerism and risk of relapse. Nevertheless, data from the literature remain contradictory and further correlations should be established, especially in RIC transplants. In this study we have analyzed the impact of MRD and chimerism monitoring on the outcome of 34 patients undergoing RIC allogeneic SCT who were considered poor candidates for conventional transplantation due to advanced age or other concurrent medical conditions. At day +100 25 (75%) patients reached complete remission (CR), there were five (15%) partial responses and three patients progressed. Incidence of grade 2-4 aGVHD and extensive cGVHD were 35% and 58%, respectively. Sixteen percent of patients developing aGVHD relapsed as compared to 47% in those without aGVHD (P = 0.03) and also 10% of patients developing cGVHD relapsed as compared to 50% relapses in those without cGHVD (P = 0.03). Four patients (12%) died due to early (n = 1) and late (n = 3) transplant-related mortality. After a median follow-up of 15 months, 24 out of the 34 patients remain alive. Projected overall survival and disease-free survival at 3 years are 68% and 63%, respectively. Early chimerism analysis showed 67% of patients with complete chimerism (CC) in bone marrow (BM), 86% in peripheral blood (PB), 89% in granulocytes and 68% in T lymphocytes. On day +100, these figures were 68%, 79%, 90% and 73%, respectively, and on day +180 there were 83% patients with CC in BM, 100% in PB, 100% in granulocytes and 100% in T lymphocytes. We observed a trend to a higher incidence of relapse in patients with mixed chimerism (MC) as compared to patients with CC. MRD monitoring by flow cytometry and/or RT-PCR analysis was performed in 23 patients. MRD assessment on days +21 to +56 after transplant allowed identification of patients at risk of relapse. In this sense, seven out of 12 patients (58.3%) who had positive MRD on days +21 to +56 relapsed as compared to none out of 11 patients who had negative MRD (P = 0.002). Of the seven patients with criteria to monitor MRD who relapsed after transplant, all but one remained MRD positive until relapse. By contrast, 10 patients remained MRD negative and all of them are in continuous CR. In nine additional patients, persistence of MRD or mixed chimerism was observed after transplant and withdrawal of cyclosporin with or without DLI was performed. Only two out of these nine patients relapsed. MRD clearance was preceded by CC and GVHD. In conclusion, in our study we found that RIC allogeneic transplantation can be used in patients considered poor candidates for conventional transplantation due to advanced age or other concurrent medical conditions with both low toxicity and low transplant-related mortality. Simultaneous studies of both chimerism and MRD are a useful tool in order to predict risk of relapse in patients undergoing RIC transplants and so can be helpful for individualizing treatment strategies after transplant.     

Noninvasive Monitoring of Mantle Cell Lymphoma by Immunoglobulin Gene Next-Generation Sequencing in a Phase 2 Study of Sequential Chemoradioimmunotherapy Followed by Autologous Stem-Cell Rescue

BackgroundMinimal residual disease (MRD) monitoring has been used to identify early molecular relapse and predict clinical relapse in mantle cell lymphoma (MCL). Few published data exist in MCL on the performance of next-generation sequencing–based assay of immunoglobulin gene rearrangements for MRD assessment.Patients and MethodsIn a prospective clinical trial (NCT01484093) with intensive induction chemotherapy and autologous stem-cell transplantation, posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with an earlier version of the Adaptive Biotechnologies MRD assay.ResultsOf the 7 patients whose disease remained in remission, the MRD test remained negative in 5 (71%). Of the 9 patients who experienced relapse, the MRD test was positive at least 3 months before relapse in 6 patients (67%) and positive at the time of relapse in 1 patient (11%). All patients with at least 2 positive MRD tests experienced relapse.ConclusionThe next-generation sequencing–based MRD assay identified early molecular relapse, and we observed more sensitivity in the cellular (circulating leukocytes) versus acellular (plasma cell-free DNA) compartment. This observation may be due to availability of tumor target or a limitation of the assay.     

Clinical Analysis of Pediatric T-Cell Acute Lymphoblastic Leukemia Using the MRD-Oriented Strategy System

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) has historically been associated with a poor prognosis. However, prognostic indicators and methods of treatment used for T-ALL remain controversial. A total of 136 children newly diagnosed with T-ALL between 2005 and 2018 were consecutively enrolled in this study. We assessed the effect of different prognostic factors, such as clinical characteristics, minimal residual disease (MRD), and the role of transplantation in postremission treatment, as the outcomes. Compared with B-ALL patients, patients with T-ALL are generally older, more likely to be male and have a higher white blood cell count. The complete remission (CR) rate was 95.6%, while the 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 74.3 ± 3.7%, 71.3 ± 3.9%, and 24.4 ± 3.8%, respectively. In the multivariate analysis, day 33 MRD ≥0.1% and hyperleukocytosis were associated with a significantly worse prognosis in the whole group. Transplantation resulted in a significant survival advantage, compared with chemotherapy, for high-risk (HR) patients (5-year CIR: 15.6 ± 10.2% vs. 55.6 ± 11.7%, P = .029). The prognosis of children with T-ALL was poor, and the MRD on day 33 was found to be an important predictive factor of clinical outcome at our center.     

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.     

Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2-deoxycoformycin and prediction of early relapse.

The purine nucleoside analogues 2-chlorodeoxyadenosine (2-CdA) and 2'-deoxycoformycin (2'-DCF) induce complete remission (CR) in the majority of patients with hairy cell leukemia. However, minimal residual disease (MRD) has been detected in bone marrow core biopsies using immunohistochemical techniques in patients achieving CR by conventional criteria. This study was designed to compare the prevalence of MRD with each agent in patients in CR by using conventional criteria and the relapse-free survival for patients with and without MRD. Bone marrow biopsies from 39 patients treated with a single cycle of 2-CdA and 27 patients treated with multiple cycles of 2'-DCF were studied. The monoclonal antibodies anti-CD20, DBA.44, and anti-CD45RO were used to evaluate the paraffin-embedded bone marrow core biopsies for MRD. Five of 39 patients (13%) treated with 2-CdA had MRD, as compared to 7 of 27 patients (26%) treated with 2'-DCF (two-tailed P = 0.21). Relapse has occurred in two of the five patients with MRD after 2-CdA treatment and in four of the seven patients with MRD after 2'-DCF treatment. In total, 6 of the 12 patients (50%) with MRD have relapsed, whereas 3 of 54 patients (6%) without MRD have relapsed, and 2 patients have died without evidence of relapse. The estimated 4-year relapse-free survival among patients with MRD is 55% (+/- 15%, SE), compared to 88% (+/- 5%, SE) among patients without MRD (two-tailed P = 0.0023). The prevalence of MRD detected in a subset of patients in CR after either 2-CdA or 2'-DCF treatment did not differ significantly. However, the presence of MRD is associated with an increased risk of relapse.     

WT1基因与急性髓系白血病的预后及主动特异性免疫治疗的研究进展

WT1基因位于人类染色体11p13，在80%的急性髓系白血病（acute myeloid leukemia，AML）患者中高表达，是AML预后不良的分子标志，可作为AML预后评估和微小残留病变（minimal residual disease，MRD）监测的有效指标。由于WT1在AML中均有异常高表达，故认为是一种AML抗原，可作为特异性免疫治疗的新靶点。一些小规模的临床试验证实以WT1为靶点的免疫治疗是有效的、安全的，这些免疫治疗可作为那些有高危复发风险及初始标准化疗失败的AML患者的辅助治疗。本文就近几年WT1与AML的预后及有关以WT1为靶点的主动特异性免疫治疗的研究进展予以综述。     

PCR-heteroduplex analysis of TCR gamma, delta and TAL-1 deletions in T-acute lymphoblastic leukemias: implications in the detection of minimal residual disease

Detection of MRD remains one of the major goals in the treatment of acute lymphoblastic leukemia (ALL). We have used the polymerase chain reaction (PCR)-heteroduplex (HD) analysis to assess and confirm the clonal expansion of T cell receptor (TCR) gamma and delta gene rearrangements in 24 T-ALL patients at diagnosis. 52.4% revealed Vdelta1-Jdelta1; 48% Vdelta2-Ddelta3; 62.5% Vgamma1-Jgamma1 and 46% both Vdelta1-Jdelta1 and Vgamma1-Jgamma1 clonal rearrangements. 6/24 patients had TAL-1 deletion. These clonal markers were used to monitor MRD in remission/relapse bone marrow samples for periods ranging from 6 to 75 months after diagnosis. Patients who relapsed and died revealed a continuous PCR-HD positivity in their clinical remission bone marrow samples. HD analysis established identical diagnostic clone at relapse. Patients who are in long-term clinical and morphological remission achieved PCR-HD negativity in their 8-12 months bone marrow remission samples and continue to be PCR-HD negative. MRD monitored in six patients with two diagnostic PCR--HD positive clonal markers reveal an identical pattern ensuring circumvention of false positive and negative results. Thus, we conclude that PCR followed by HD analysis is a useful technique to monitor MRD in remission/relapse samples in ALL patients.     

Importance of minimal residual disease testing during the second year of therapy for children with acute lymphoblastic leukemia.

PURPOSE: A high level of minimal residual disease (MRD) after induction chemotherapy in children with acute lymphoblastic leukemia (ALL) is an indicator of relative chemotherapy resistance and a risk factor for relapse. However, the significance of MRD in the second year of therapy is unclear. Moreover, it is unknown whether treatment intervention can alter outcome in patients with detectable MRD. PATIENTS AND METHODS: We assessed the prognostic value of MRD testing in bone marrow samples from 85 children at 1, 12, and 24 months from diagnosis using clone-specific polymerase chain reaction primers designed to detect clonal antigen receptor gene rearrangements. These children were part of a multicenter, randomized clinical trial, which, in the second year of treatment, compared a 2-month reinduction-reintensification followed by maintenance chemotherapy with standard maintenance chemotherapy alone. RESULTS: MRD was detected in 69% of patients at 1 month, 25% at 12 months, and 28% at 24 months from diagnosis. By univariate analysis, high levels of MRD at 1 month, or the presence of any detectable MRD at 12 or 24 months from diagnosis, were highly predictive of relapse. Multivariate analysis showed that MRD testing at 1 and 24 months each had independent prognostic significance. Intensified therapy at 12 months from diagnosis did not improve prognosis in those patients who were MRD positive at 12 months from diagnosis. CONCLUSION: Clinical outcome in childhood ALL can be predicted with high accuracy by combining the results of MRD testing at 1 and 24 months from diagnosis.     

Prognostic significance of monitoring leukemia-associated immunophenotypes by eight-color flow cytometry in adult B-acute lymphoblastic leukemia

Minimal residual disease (MRD) is of the most important factor for predicting prognosis and guiding treatment of acute lymphoblastic leukemia (ALL). In this study, we investigated the prognostic significance of leukemia-associated immunophenotypes (LAIPs) as assessment of index of MRD in 125 adult B-lineage ALL (B-ALL) patients by eight-color flow cytometry. The LAIPs could be identified in 96% and 81.6% of patients with the sensitivity of 10⁻⁴ and 10⁻⁵, respectively. MRD-negative status could clearly predict a favorable 2-year relapse-free survival (RFS) and overall survival (OS) at the end of induction of complete remission and one cycle of consolidation treatment. Moreover, we identified a group of cases with MRD of 0.001% to <0.01%, which showed significantly higher 2-year relapse rate than those with undetectable one. In multivariate analysis, MRD status was associated with RFS or OS independently. Furthermore, MRD assessed by LAIPs and RQ-PCR assay for patients with BCR-ABL fusion gene yielded concordant results in 89.7% of cases. In conclusion, MRD evaluated by eight-color flow cytometry could provide an important tool to assess treatment response and prognosis precisely in adult B-ALL.     

Cladribine- and decitabine-containing conditioning regimen has a low post-transplant relapse rate in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning regimens. Our study aimed to analyze the risk factors associated with the relapse of relapsed/refractory (R/R), high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) post-transplant and the efficacy of a new conditioning regimen involving decitabine and cladribine. Clinical data of 125 patients with R/R AML, high-risk AML and high-risk MDS who underwent allo-HSCT were collected. In addition, 35 patients with R/R AML, high-risk AML and high-risk MDS received treatment with a new conditioning regimen including decitabine and cladribine. Cox regression analysis was used to identify risk factors associated with OS, RFS and relapse. Among 125 patients who underwent allo-HSCT, CR before allo-HSCT and matched sibling donors were independent protective factors for OS. DNMT3A abnormality was an independent risk factor for both relapse and RFS. Among 35 patients who received a new conditioning regimen containing decitabine and cladribine, only six patients relapsed and 1-year cumulative incidence of relapse was 11.7%. Moreover, this new regimen showed efficient MRD clearance early after allo-HSCT. The combined decitabine- and cladribine-based conditioning regimen showed a low relapse rate and a high survival without an increased incidence of GVHD or adverse effects and thus has potential for use in allo-HSCT for R/R AML, high-risk AML and high-risk MDS.     

Monitoring bcr-abl by polymerase chain reaction in the treatment of chronic myeloid leukemia

The elucidation of the molecular biology of chronic myeloid leukemia (CML) has provided a paradigm for understanding leukemogenesis, targeted drug development, and disease monitoring at the molecular level. Minimal residual disease (MRD) monitoring by fluorescence in situ hybridization and polymerase chain reaction (PCR) has become an important tool in predicting relapse after allogeneic transplant, allowing for early intervention strategies such as donor lymphocyte infusion. MRD monitoring is important for assessment of disease status in patients who obtain a complete cytogenetic remission, and this approach is likely to play an important role in following patients to determine who will relapse on imatinib mesylate therapy. This review focuses primarily on MRD monitoring by PCR.     

Relapse in Hodgkin lymphoma

The retrospective study revealed the 15% relapse rate in patients with stage II-IV unfavorable prognosis Hodgkin lymphoma, 5-year OS in relapsed patients was 84%. Karnofsky score less than 80 (p=0,0001), more than 1 extranodal lesion (p=0,0004), extensive (equal to stage III-IV) involvement on relapse (p=0,001), b-symptoms on relapse (p=0,023), more than 5 lymph nodal lesions (p=0,027), albumin level less than 40 g per liter (p=0,037), detection of new nodal lesions (p=0,041) were shown by discriminative analysis as the therapy effect predictors in patients with Hodgkin lymphoma relapse. In patients with second-line therapy failure the actuarial survival rate was lower by 55% in comparison to patients with chemosensitive relapses (40% and 95%). The secondary therapy resistance was shown to be an unfavorable prognosis predictive factor (p=0,0001). The multifactorial overall survival analysis revealed the following adverse prognostic factors: failure of second-line treatment (p=0,0001), first early relapse (p=0,01), albumin level on relapse less than 40 g per liter (p=0,02), use of standard chemotherapy instead of irradiation (p=0,02). The relapse patients with 1 or less risk factors had 95% 5-year OS, the patients with 3 or more adverse risk factors had 70% OS (p=0,0002). The lowest 10-year OS was observed in patients with 2 or more adverse risk factors, 48% and 28% accordingly. Adverse risk factors must be considered while choosing the optimal treatment strategy aimed at better survival rate.     

Minimal residual disease in early phase of chemotherapy reflects poor outcome in children with acute lymphoblastic leukemia--a retrospective study by the Children's Cancer and Leukemia Study Group in Japan

We analyzed the minimal residual disease (MRD) in 50 children with acute lymphoblastic leukemia (ALL) by amplifying the clonally rearranged T-cell receptor (TCR) gamma/delta chain and/or immunoglobulin (Ig) kappa chain gene using the allele-specific-PCR method. All children were treated according to the protocols of the Children's Cancer and Leukemia Study Group of Japan (CCLSG). The patients were stratified into four risk-groups according to the leukocyte count and age at diagnosis. We prospectively sampled the patients' bone marrow at 1 month (point 1) and 3 months (point 2) after the initiation of chemotherapy and quantitated the MRD retrospectively. The results of MRD were closely related with the clinical outcome. The relapse rate of the patients MRD-positive at points 1 and 2 was 46% (6/13) and 86% (6/7), respectively, whereas those MRD-negative results at point 1 and 2 were 13% (3/13) and 3% (3/30), respectively. We found significant differences in the event-free survival between MRD-positive children and MRD-negative children like the reports, which have been made by BFM and EORTC groups. We conclude that MRD in an early phase of chemotherapy can be a good predictor of the prognosis of childhood ALL regardless of the protocol of chemotherapy or race.     

Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma

BACKGROUND: Although > 90% of children with nonmetastatic rhabdomyosarcoma (RMS) achieve complete remission with current treatment, up to one-third of them experience a recurrence. Survival rates are not always poor in patients who develop recurrences; thus, prognostic factors are needed to tailor salvage treatment. METHODS: The current analysis included 125 children who were affected by localized RMS and were enrolled in 3 consecutive Italian protocols (RMS79, RMS88, and RMS96) who developed recurrences after complete remission. Patient, tumor, and treatment characteristics were studied in univariate and multivariate analyses to determine the independent significance of different factors. RESULTS: The median time from diagnosis to recurrence was 17.8 months. Most patients had local recurrences (72%). The 5-year overall survival (OS) rate was 28.3% +/- 8.7%. Multivariate analysis identified 4 factors that were associated with poor survival: 1) alveolar subtype (relative risk [RR], 2.0), 2) parameningeal or "other" sites (RR, 2.6), 3) systemic recurrence (RR, 3.1), and 4) recurrence on therapy (RR, 2.3). The absence of any of these risk factors identified a "favorable risk" group (12% of patients) with a 5-year OS rate of 71.8% +/- 23.5%. Patients with a single risk factor (32%) had an OS rate of 37.5% +/- 17.2%. Combining patients with 0 or 1 risk factor, the OS rate was 66.5% in the subgroup who had not received radiotherapy compared with an OS rate of 30.3% in the subgroup who had received radiotherapy; this difference was significant (P = 0.03). CONCLUSIONS: The results of the current analysis demonstrated that groups with a different prognosis can be identified among patients with recurrent RMS. Patients with a nonalveolar histology, a primary site other than the parameningeal or "other" sites, local recurrence, and recurrence off therapy had a better prognosis. First-line treatment may have an impact on prognostic variables. In fact, patients who had no or only one risk factor and patients who had tumors with a nonalveolar histology benefited more from salvage therapy if they had not received radiotherapy for their initial treatment. These data may be useful in planning risk-adapted salvage protocols.     

急性髓细胞性白血病患者微小残留病流式细胞术检测的临床意义

 目的　探讨流式细胞术检测急性髓细胞性白血病（AML）微小残留病（MRD）的临床意义。方法　对21例生存24～128个月成年人AML完全缓解（CR）患者,采用双色直接免疫荧光标记及多参数流式细胞术每隔3～12个月检测一次外周血中MRD,同时检测骨髓细胞形态的变化。结果　21例动态检测MRD水平>10-4患者复发率为80.0 %,MRD水平≤10-4患者复发率为18.1 %。21例随访24 ~ 128个月,复发10例,其中有3例先髓外复发,未复发有11例。10例MRD水平>10-4患者24个月EFS率为30.0 %;11例MRD水平≤10-4患者为90.9 %。MRD水平≤10-4患者中复发的2例,分别在MRD水平升为10-2后3个月、7个月时出现骨髓复发。结论　MRD水平为10-3或以上的患者预后较差,易复发。MRD水平长时间波动在10-3～10-4间,即使骨髓无复发,也要警惕髓外复发。MRD水平≤10-4者生存期长,预后较好。但在生存期超过5年停化疗后,仍应动态监测MRD水平,尤其当MRD水平升至10-2水平时应警防复发,甚至考虑采用干预治疗。     

Prognostic factors in patients progressing after cisplatin-based chemotherapy for malignant non-seminomatous germ cell tumours.

The aim of this study was to define prognostic parameters for survival in patients with malignant germ cell tumours progressing after platinum-based induction chemotherapy with or without surgery. A total of 164 progressing patients (testicular: 83%, extragonadal: 17%) were identified out of 795 patients treated with platinum-based induction chemotherapy for metastatic germ cell malignancy with or without surgery. 'Progressive disease' included patients who had progressed after a previous partial or complete remission as well as patients who failed primary therapy. Salvage chemotherapy consisted of 'conventional' platinum-based chemotherapy. Prognostic factors for survival were assessed by uni- and multivariate analyses. The resulting prognostic model was validated in an independent data set of 66 similar patients. For all 164 patients the median time from start of induction chemotherapy to progression was 10 months (range: 0-99). Thirty-eight (23%) patients relapsed after 2 years. The 5-year survival rate for all progressing patients was 30% (95% confidence interval 23-38%). In the univariate analysis the following factors most importantly predicted a poor prognosis: progression-free interval < 2 years: initial poor prognosis category (MRC criteria), < CR to induction chemotherapy, initial treatment early in the 1980s and treatment given at a 'small' centre. Three prognostic factors remained in the multivariate analysis: progression-free interval, response to induction treatment and the level of serum human chronic gonadotrophin (hCG) and alpha fetoprotein (AFP) at relapse. One hundred and twenty-four patients could be classified on the basis of these characteristics, Those patients with progression-free interval < 2 years, < CR to induction chemotherapy and high markers at relapse (AFP >100 kU l(-1) or hCG >100 IU l(-1)) formed a poor prognosis group of 30 patients, none of whom survived after 3 years. Patients with at most two of these three risk factors formed a good prognosis group of 94 patients (76%) with a 47% (37-56%) 5-year survival. Thirty-eight patients from the good prognosis group with a progression-free interval of >2 years had a 2-year survival of 74% (60-88%) and 5-year survival of 61%. These prognostic groups were validated in the independent data set, in which 5-year survival rates in the good and poor risk groups were 51% and 0% respectively. One-third of patients progressing during or after platinum-based induction chemotherapy for metastatic germ cell malignancy may be cured by repeated 'conventional' platinum-based chemotherapy. Good prognosis parameters are: progression-free interval of > 2 years, CR to induction treatment and normal or low serum markers at relapse (hCG < 100 IU l(-1) and AFP < 100 kU l(-1)). The results of high-dose salvage chemotherapy should be interpreted on the background of these prognostic factors.     

Prognostic significance of young age in breast cancer

BACKGROUND: Breast carcinoma is relatively uncommon in younger women and whether or not young age at diagnosis is an adverse prognostic factor in this disease has been controversial. Our aim in this report is to determine whether the histopathologic features and outcome in young and old are different, and whether age is a prognostic factor for relapse. METHODS: A retrospective study of consecutive 281 stage I or II breast carcinoma patients who had modified radical mastectomy was carried out. The patients with a median follow-up period of 45 months were divided two groups according to their ages. The histopathological features and survival of Group 1 and Group 2 were compared with each other. Univariate and multivariate prognostic factor analysis for relapse were carried out. RESULTS: The patients in Group 1 (younger than 35 years of age) had the worst histopathological features related to the prognosis than those in Group 2 and the difference between the two groups was statistically significant. Whereas the rates of 5-year overall survival were 65% in Group 1 and 98% in Group 2 (P < 0.05), the rates of 5-year relapse-free survival were 40% and 80%, respectively (P < 0.05). In univariate analysis of all patients, pathologic tumour size, pathologic axillary status, number of metastatic lymph nodes, pathologic stage, age, lymphatic vascular invasion were statistically significant factors associated with relapse. Multivariate analysis demonstrated that number of metastatic nodes (risk ratio RR:4.3 in more than three nodes) and age (RR:3.6 in Group 1) were the most important independent prognostic factors for relapse. In the patients without axillary involvement, both of univariate and multivariate analysis revealed that pathologic tumour size (RR:5.1 in pT(2)) and age (RR:4 in Group 1) were the independent prognosticators for relapse. CONCLUSIONS: Young patients with breast cancer had the worst histopathological features and the worst survival than their older counterparts. Age was an independent significant prognostic factor for relapse.     

Pretransplant minimal residual disease level predicts clinical outcome in patients with acute myeloid leukemia receiving high-dose chemotherapy and autologous stem cell transplantation.

A total of 31 adult patients with AML entered in the EORTC/GIMEMA AML-10 trial, who received autologous stem cell transplantation (ASCT) after induction and consolidation chemotherapy, were prospectively evaluated for minimal residual disease (MRD) by multidimensional flow cytometry (MFC). Using a cutoff level of 3.5 x 10(-4) leukemic cells pre-ASCT, 12 patients (39%) were stratified to MRD high-risk group and 19 (61%) into MRD low-risk group. During follow-up, all patients who were in the high-risk group relapsed at a median time of 7 months; in the low-risk group, five patients relapsed at a median time of 11 months and 14 remained in remission for 56 (range 7-80) months (P=0.00004). Longitudinal MFC determinations post-ASCT showed increased MRD levels in three of the five patients who underwent subsequent relapse, while disease recurrence was unpredicted in the remaining two cases. The pre-ASCT MRD status was the factor most strongly associated with relapse risk in the multivariate analysis (P=0.0014). We conclude that: (1) pre-ASCT MRD status predicts successful outcome in patients receiving ASCT; (2) high-dose chemotherapy conditioning regimen followed by ASCT has no impact on the unfavorable prognostic value of high pre-ASCT MRD level; and (3) sequential MRD monitoring post-ASCT may allow the prediction of impending relapse.