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Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young a...
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Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2·5 cycles (range 1-4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long-term CR.
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Abstract Background/Aims We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of ...
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Abstract Background/Aims We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft‐versus‐host disease (GVHD) on OSR. Methods Data on 386 patients from nine Australian centres with relapsed AML post‐alloHSCT were collected retrospectively. OSR was calculated using the Kaplan–Meier method. Univariate and multivariate analyses were conducted using the log‐rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. Results On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P ?<?0.001) and grade 3–4 acute GVHD preceding relapse (HR 2.0, P ?=?0.004), were associated with inferior OSR. Patients with 1–2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P ?<?0.001, patients given salvage: HR 1.8, P ?<?0.001). The first salvage therapy used post‐relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re‐induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon‐α in 6. Although re‐induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P ?<?0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy ( P ?=?0.405). Conclusion Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3–4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.
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Abstract Background/Aims We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of ...
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Abstract Background/Aims We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft‐versus‐host disease (GVHD) on OSR. Methods Data on 386 patients from nine Australian centres with relapsed AML post‐alloHSCT were collected retrospectively. OSR was calculated using the Kaplan–Meier method. Univariate and multivariate analyses were conducted using the log‐rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. Results On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P ?<?0.001) and grade 3–4 acute GVHD preceding relapse (HR 2.0, P ?=?0.004), were associated with inferior OSR. Patients with 1–2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P ?<?0.001, patients given salvage: HR 1.8, P ?<?0.001). The first salvage therapy used post‐relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re‐induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon‐α in 6. Although re‐induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P ?<?0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy ( P ?=?0.405). Conclusion Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3–4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.
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Induction regimens integrating cladribine or fludarabine have shown promising outcomes in relapsed or refractory (R/R) acute myeloid leukaemia (AML). We compared the outcome of a cladribine-versus a fludarabine-based regimen as in...
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Induction regimens integrating cladribine or fludarabine have shown promising outcomes in relapsed or refractory (R/R) acute myeloid leukaemia (AML). We compared the outcome of a cladribine-versus a fludarabine-based regimen as induction chemotherapy for R/R-AML. We included patients with R/R-AML who were treated with a cladribine-or fludarabine-based chemotherapy between 2006 and 2015. We analysed 120 patients, 65 treated with cladribine and 55 treated with fludarabine. The CR rates were 62.7 and 61.4 % for the cladribine group and fludarabine group, respectively (p = 0.890). Poor prognostic factors included older age, secondary AML, poor cytogenetic risk group, prior induction failure, and short first CR duration. No significant overall survival (OS) or relapse-free survival (RFS) differences were found between the groups (OS, p = 0.213; RFS, p = 0.143). However, in a certain subset, survival outcomes were better with cladribine than with fludarabine, including de novo AML, CR at first induction therapy, and not-poor cytogenetic risk group inclusion without overt chemotherapy-refractoriness. By contrast, secondary AML patients had improved survival outcomes when treated with the fludarabine regimen. After CR, better outcomes were observed when allogeneic stem cell transplantation (SCT) was given as consolidation. In R/R-AML, cladribine-and fludarabine-based combination induction chemotherapy had differential survival outcomes according to disease characteristics. Allogeneic SCT after CR with a purine analogue-based regimen improved long-term outcome in these patients.
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Purpose of reviewRelapse of haematological neoplasms after allogeneic haematopoietic stem cell transplantation (HSCT) remains one of the leading causes of death. Treatment of relapse post-HSCT is frequently ineffective and outcome...
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Purpose of reviewRelapse of haematological neoplasms after allogeneic haematopoietic stem cell transplantation (HSCT) remains one of the leading causes of death. Treatment of relapse post-HSCT is frequently ineffective and outcomes are poor, necessitating preventive strategies that are reviewed below.Recent findingsCurrent strategies to prevent relapse after HSCT are geared towards four general principles: improving the antitumour effects of conditioning regimens prior to HSCT, improving graft selection and engineering to augment the graft-versus-leukaemia effect, post-HSCT chemotherapeutic interventions to impair growth of residual clonal cells and post-HSCT immune-mediated interventions to enhance the graft-versus-leukaemia effect. Strategies based on cell manipulation, namely natural killer (NK) cell enrichment and adoptive T cell transfer, are emerging. Targeted therapies including vaccinations, FLT3 inhibitors, mAbs and chimeric antigen receptor T cell therapy represent a new avenue of treating acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Studies are underway to incorporate all of these strategies in the clinical setting to determine their impact on relapse and survival after HSCT.SummaryThe most recent evidence suggests that strategies using NK cell therapy and targeted immune therapies after HSCT may change the current landscape of HSCT for AML and MDS.
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We hereby report our multicentre, retrospective experience with CLARA in patients with fludarabine/cytarabine/GCSF (FLAG) refractory AML. The study included all consecutive R/R AML patients, who received CLARA salvage during Octob...
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We hereby report our multicentre, retrospective experience with CLARA in patients with fludarabine/cytarabine/GCSF (FLAG) refractory AML. The study included all consecutive R/R AML patients, who received CLARA salvage during October 2010-October 2015 period. All patients were unresponsive to FLAG salvage chemotherapy regimen and did not undergo previous allo-HCT. A total of 40 patients were included. Following CLARA 5 (12.5%) patients experienced induction mortality and 10 (25%) patients achieved CR. 25 (62.5%) patients were unresponsive to CLARA. 7 (17.5%) out of 10 patients in CR received allo-HCT. Median overall survival of patients who achieved CR after CLARA was 24.5 months (8.5-54.5) and 3 months (2.5-5), in patients who underwent and didn't allo-HCT, respectively. Our results indicate that CLARA may be good alternative even in FLAG refractory AML patients and can be used as a bridge to allo-HCT, who have a suitable donor and able to tolerate the procedure.
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CD25+ CD34+ CD38- leukaemic cells have been shown to be chemotherapy-resistant and initiate acute myeloid leukaemia (AML) in xenograft models, suggesting a leukaemic stem cells (LSC) biology (Saito et al, 2010). High CD25 (also kn...
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CD25+ CD34+ CD38- leukaemic cells have been shown to be chemotherapy-resistant and initiate acute myeloid leukaemia (AML) in xenograft models, suggesting a leukaemic stem cells (LSC) biology (Saito et al, 2010). High CD25 (also known as interleukin 2 receptor alpha, IL2RA) expression (>10%) at diagnosis in young (<60 years) AML patients in retrospective analysis correlated with a significantly shorter overall survival (OS, P = 0-0005) and relapse-free survival (RFS, P = 0-005). CD25 expression was also associated with FLT3-internal tandem duplication (ITD) mutation, and double positive patients had the poorest OS and RFS (P = 0-001 and P = 0-003, respectively; Terwijn et al, 2009).
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Between 30% and 40% of myelodysplastic syndrome (MDS) patients progress to acute myeloid leukaemia (AML). The prognosis of these secondary AML (sAML) cases is poor with frequent resistance to conventional chemotherapy and an overa...
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Between 30% and 40% of myelodysplastic syndrome (MDS) patients progress to acute myeloid leukaemia (AML). The prognosis of these secondary AML (sAML) cases is poor with frequent resistance to conventional chemotherapy and an overall survival of <1 year (Nimer, 2008). Epigenetic deregulation has recently been demonstrated as one of the driving phenomena during disease progression (Jiang et al, 2009). Demethylating agents lead to significant clinical benefit for both MDS and AML patients (Fenaux et al, 2009) and represent an attractive option for AML arising after MDS. Nevertheless, a majority of patients fail to respond to azacitidine (AZA) and most responders progress within 2 years (Fenaux et al, 2010). There is no standard of care for salvage therapy after AZA failure and investigational agents have been extensively studied. We recently showed that the outcome of high risk MDS after AZA failure was poor (Prebet et al, 2011), with a median overall survival (OS) of 5.6 months but, to date, the outcome of sAML after AZA failure has not been described, representing a potential limitation for the design and interpretation of clinical studies. We therefore analysed the outcome of 74 patients with sAML after AZA treatment failure, collected from two Johns Hopkins University trials (J9950 and J0443, n = 14) (Gore et al, 2006; Fandy et al, 2009) and the French AZA compassionate programme (n = 60) (Itzykson et al, 2011). Inclusion criteria were: (i) diagnosis of AML arising from MDS according to the French-American-British classification; (ii) 30% or more bone marrow blasts before AZA onset; (iii) having received at least one cycle of AZA.
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Despite improvements in diagnosis and treatment, 30-40% of children with acute myeloid leukaemia (AML) experience relapse. For those who relapse after allogeneic haematopoietic stem cell transplantation (allo-HSCT), the prognosis ...
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Despite improvements in diagnosis and treatment, 30-40% of children with acute myeloid leukaemia (AML) experience relapse. For those who relapse after allogeneic haematopoietic stem cell transplantation (allo-HSCT), the prognosis is particularly poor, with limited reported literature on these patients. We reviewed the clinical course of 49 children with AML (28 males, 21 females) who received allo-HSCT between 1993 and 2011, and who had subsequently relapsed. Study endpoints included (i) complete remission (CR) rate after intensive chemotherapy, and prognostic factors for CR, (ii) disease-free survival (DFS) and overall survival (OS) for patients who achieved CR and (iii) OS for recipients of intensive chemotherapy and prognostic factors for OS. Of the 36 patients who received intensive chemotherapy after post-HSCT relapse, 26 (72%) achieved CR. For patients who achieved CR, 5-year DFS and OS were 32·6 ± 10·2% and 44·4 ± 11·1%, respectively. For all recipients of intensive chemotherapy, 5-year OS was 31·6 ± 8·7%. Cumulative incidence of treatment-related death was 14·4%. All three recipients of second HSCT died. Amongst prognostic factors predicting improved survival, only disease status at HSCT (early first CR vs. others) proved significant in multivariate study (Hazard Ratio 2·42, 95% Confidence Interval 1·02-5·74, P = 0·045). Treatment with curative intent was able to salvage a minor but important subset of children with AML who relapsed post-allogeneic transplant.
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Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and...
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Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and biological data, and final outcome of 48 paediatric patients with primary-resistant AML enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 clinical trial. These patients had a significantly higher white blood cell count at diagnosis compared to other AML patients. Cytogenetic and molecular features did not differ between patients with primary induction failure and patients allocated to the high-risk group. For the whole patient population, the probability ofoverall survival, event-free survival (EFS) and disease-free survival (DFS)was 21.8%+/- 6.2, 20.4%+/- 5.9, and 49.5%+/- 11.3, respectively. Twenty-eight (58%) patients received haematopoietic stem cell transplantation (HSCT); 3 were autologous and 25 were allogeneic. Patients who underwent HSCT had improved EFS (31.2% vs. 5%, P<0.0001). Only one of the20 patients who did not receive HSCT is alive and disease free. The 19 patients in complete remission at time of HSCT showed significantly betterDFS than the 9 with active disease (46% vs. 0%, P=0.02). This study represents one of the largest series with long-term follow up of paediatric AML patients with primary refractory disease. Children who underwent transplantation had an encouraging long-term outcome. Disease recurrence remains the major cause of treatment failure; a better understanding of the disease biology is desirable to develop more effective treatment strategies.
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