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The prognosis of patients with relapsed and refractory acute leukaemia (RRAL) is very poor. Forty patients with RRAL were enroled [28 acute myeloid leukaemia (AML), 12 acute lymphoblastic leukaemia (ALL)] in this Phase 1 dose-esca...
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The prognosis of patients with relapsed and refractory acute leukaemia (RRAL) is very poor. Forty patients with RRAL were enroled [28 acute myeloid leukaemia (AML), 12 acute lymphoblastic leukaemia (ALL)] in this Phase 1 dose-escalation trial of daily-infused clofarabine (CLO) followed by cyclophosphamide (CY) for four consecutive days (CLO-CYx4). The median age was 48·5 years. The median number of prior regimens was 2 (range 1-5), and 6/40 patients (15%) had prior allogeneic haematopoietic stem cell transplant. 28/40 patients (70%) had adverse genetic features. 6/40 patients (15%) died within 60 d of induction (two infections, four progressive disease). The average time to neutrophil recovery (absolute neutrophil count ≥0·5 × 10 9/l was 34 d, (range, 17-78). The overall response rate (ORR) was 33% (13/40), with seven complete remissions (18%), four complete remissions with incomplete recovery of blood counts (10%), and two partial remissions (5%). ORR was 25% (7/28), and 50% (6/12), for AML and ALL respectively. Notably, the clinical responses were independent of dose level. 7/17 patients (41%) exhibited CLO-mediated enhancement of CY-induced DNA, which was associated with, but not necessary for, improved clinical outcomes. In summary, the CLO-CYx4 regimen was well tolerated and had activity in patients with RRAL, especially relapsed ALL. Therefore, CLO-CYx4 can be considered a salvage therapy for adults with RRALs, and warrants further investigations.
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As front line therapy has improved, the treatment of relapsed chronic lymphocytic leukaemia has become more difficult as the disease becomes resistant and the patient accumulates comorbidities. The outcome for those who relapse af...
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As front line therapy has improved, the treatment of relapsed chronic lymphocytic leukaemia has become more difficult as the disease becomes resistant and the patient accumulates comorbidities. The outcome for those who relapse after immunochemotherapy with fludarabine, cyclophosphamide and rituximab is strongly influenced by the duration of initial response. Patients who relapse within the first year or with a TP53 abnormality have very high-risk disease and will not respond to chemotherapy. High dose glucocorticoid and alemtuzumab followed by an allogeneic stem cell transplant is probably the best approach for younger, fitter patients in this category. Those who relapse after 2-3 years without TP53 abnormality will probably respond to their initial therapy again. Relapse within 12-24 months carries an intermediate outlook. Additional options include bendamustine and rituximab, ofatumumab and lenalidomide. New therapies are on the horizon and patients should be discussed with a specialist centre and entered into a clinical trial whenever possible.
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Abstract The probability of achieving long term remission for patients with refractory acute leukaemia is very low. Allogeneic stem cell transplantation (SCT) is offered to these patients in order to improve their dismal outcome. ...
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Abstract The probability of achieving long term remission for patients with refractory acute leukaemia is very low. Allogeneic stem cell transplantation (SCT) is offered to these patients in order to improve their dismal outcome. We retrospectively analyzed 361 acute leukaemia patients, who underwent allogeneic SCT in the Hadassah's bone marrow transplantation department between the years 2005 and 2012 and identified 84 patients with active leukaemia at transplantation. Median age was 34?years. Sixty four patients were diagnosed with acute myeloid leukaemia (AML), 18 patients with acute lymphoblastic leukaemia and two with biphenotypic leukaemia. The majority of patients were diagnosed with de‐novo AML and transplanted at relapse. In the surviving patients, median follow up was 15?months. One year OS was 20%. At time of last follow up, 13 patients were alive (15.5%): ten patients with AML and two patients with acute lymphoblastic leukaemia. In the univariate analysis, factors associated with significantly better overall survival were as follows: matched unrelated donor ( p ?=?0.006), matched donor ( p ?=?0.014) and occurrence of acute graft‐versus‐host disease (aGVHD) ( p ?=?0.019). Karnofsky performance score at SCT and occurrence of cGVHD were found to be borderline significant. Only matched unrelated donor and aGVHD were found to affect overall survival significantly in the multivariate analysis. Other than performance score at SCT, none of the pretransplant patients' characteristics were found to influence survival. In conclusion, as none of the pretransplant characteristics were found to influence the ability to select the patients that will benefit from HSC transplantation, this work supports offering HSCT to all active leukaemia eligible patients with reasonable performance status. Copyright ? 2016 John Wiley & Sons, Ltd.
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Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has invitro activity against ALL blasts. A phase I-II trial, reported ...
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Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has invitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (13mg/m(2)/dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (81%) died due to infections. Twenty-seven patients (729%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 01%. Twenty-two of 30 BCP-ALL patients (733%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 313%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 684%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL.
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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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Limited therapies exist for patients with refractory and relapsed (RR) higher-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukaemia with trilineage dysplasia (AML-TD). High dose (HD) lenalidomide (50 mg) has activity...
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Limited therapies exist for patients with refractory and relapsed (RR) higher-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukaemia with trilineage dysplasia (AML-TD). High dose (HD) lenalidomide (50 mg) has activity as frontline therapy in elderly AML but there is limited data in the RR setting. This phase II trial included patients with RR HR-MDS or AML-TD at 2 doses of lenalidomide (15 or 50 mg) on days 1-28 of 42-day cycles. The primary endpoint was response rate using the 2006 International Working Group criteria. Overall survival (OS) was estimated by Kaplan-Meier methods. Of 27 patients enrolled, 59% had HRMDS and 31% AML-TD. No patient had isolated del5q; 41% had poor-risk karyotype. Of 9 patients treated at 15 mg, 56% completed >= 2 cycles with no responses. Of 18 patients treated at 50 mg, 39% completed >= 2 cycles and 11% responded but all experienced grade 3/4 neutropenic fever/infection. The 60-day mortality rate was 30%. Median OS was 114 days with 19% surviving >= 1 year. The study was terminated due to lack of robust clinical activity. In conclusion, lenalidomide at 15 mg is ineffective in RR myeloid malignancies. Continous high dosing schedules are poorly tolerated and minimally active. Further evaluation should be considered in upfront intensive chemotherapy-ineligible patients.
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The definition of primary refractory acute myeloid leukaemia is the failure to achieve a response after one or two cycles of induction. Given that there are many different strategies involving different doses of cytarabine and ant...
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The definition of primary refractory acute myeloid leukaemia is the failure to achieve a response after one or two cycles of induction. Given that there are many different strategies involving different doses of cytarabine and anthracyclines, which may or may not be equivalent, and as this is an area of unmet need with the potential for the development of new agents and strategies, uniform criteria for response have been described that need to be adhered to. The outcome of patients with chemoresistant disease is poor with only a proportion of patients salvaged by allogeneic stem cell transplantation. Progress in supportive care strategies and donor identification has enabled more of these patients to undergo unrelated donor transplantation. Novel strategies and new agents directed at the biology of the disease and the mechanisms of resistance are needed.
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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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