Summary Background The standard busulfan–cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid ...leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. Methods We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40–65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days −9 through −6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days −4 and −3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days −6 through −3) and fludarabine at 40 mg/m2 per day for four consecutive days (from days −6 through −3; total dose 160 mg/m2 ). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov , number NCT01191957. Findings Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8–44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6–25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3–14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 23% of 121 patients in the busulfan plus cyclophosphamide group and 26 21% of 124 patients in the busulfan plus fludarabine group) and infections (21 17% patients in the busulfan plus cyclophosphamide group and 13 10% patients in the busulfan plus fludarabine group had at least one such event). Interpretation In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. Funding Agenzia Italiana del Farmaco.
Clinical risk classification is inaccurate in predicting relapse in adult patients with acute lymphoblastic leukemia, sometimes resulting in patients receiving inappropriate chemotherapy or stem cell ...transplantation (SCT). We studied minimal residual disease (MRD) as a predictive factor for recurrence and as a decisional tool for postconsolidation maintenance (in MRDneg) or SCT (in MRDpos). MRD was tested at weeks 10, 16, and 22 using real-time quantitative polymerase chain reaction with 1 or more sensitive probes. Only patients with t(9;22) or t(4;11) were immediately eligible for allogeneic SCT. Of 280 registered patients (236 in remission), 34 underwent an early SCT, 60 suffered from relapse or severe toxicity, and 142 were evaluable for MRD at the end of consolidation. Of these, 58 were MRDneg, 54 MRDpos, and 30 were not assessable. Five-year overall survival/disease-free survival rates were 0.75/0.72 in the MRDneg group compared with 0.33/0.14 in MRDpos (P = .001), regardless of the clinical risk class. MRD was the most significant risk factor for relapse (hazard ratio, 5.22). MRD results at weeks 16 to 22 correlated strongly with the earlier time point (P = .001) using a level of 10−4 or higher to define persistent disease. MRD analysis during early postremission therapy improves risk definitions and bolsters risk-oriented strategies. ClinicalTrials.gov identifier: NCT00358072.
Short imatinib pulses were added to chemotherapy to improve the long-term survival of adult patients with Philadelphia chromosome (Ph) -positive acute lymphoblastic leukemia (ALL), to optimize ...complete remission (CR) and stem-cell transplantation (SCT) rates.
Of 94 total patients (age range, 19 to 66 years), 35 represented the control cohort (ie, imatinib-negative IM-negative group), and 59 received imatinib 600 mg/d orally for 7 consecutive days (ie, imatinib-positive IM-positive group), starting from day 15 of chemotherapy course 1 and from 3 days before chemotherapy during courses 2 to 8. Patients in CR were eligible for allogeneic SCT or, alternatively, for high-dose therapy with autologous SCT followed by long-term maintenance with intermittent imatinib.
CR and SCT rates were greater in the IM-positive group (CR: 92% v 80.5%; P = .08; allogeneic SCT: 63% v 39%; P = .041). At a median observation time of 5 years (range, 0.6 to 9.2 years), 22 patients in the IM-positive group versus five patients in the IM-negative group were alive in first CR (P = .037). Patients in the IM-positive group had significantly greater overall and disease-free survival probabilities (overall: 0.38 v 0.23; P = .009; disease free: 0.39 v 0.25; P = .044) and a lower incidence of relapse (P = .005). SCT-related mortality was 28% (ie, 15 of 54 patients), and postgraft survival probability was 0.46 overall.
This imatinib-based protocol improved long-term outcome of adult patients with Ph-positive ALL. With SCT, post-transplantation mortality and relapse remain the major hindrance to additional therapeutic improvement. Additional intensification of imatinib therapy should warrant a better molecular response and clinical outcome, both in patients selected for SCT and in those unable to undergo this procedure.
The clinical course of polycythemia vera and essential thrombocythemia is potentially associated with long-term severe complications, such as evolution to myelofibrosis or acute myeloid leukemia. ...Allogeneic stem cell transplantation is currently the only potentially curative treatment for advanced polycythemia vera or essential thrombocythemia. We analyzed 250 consecutive patients with an initial diagnosis of polycythemia vera (n=120) or essential thrombocythemia (n=130), who underwent transplantation due to progression to myelofibrosis (n=193) or acute myeloid leukemia (n=57) and who were reported to the European Group for Blood and Marrow Transplantation registry between 1994 and 2010. Their median age was 56 years (range, 22-75) and in 52% of cases the interval between diagnosis and transplantation was 10 years or more. With a median follow-up from transplantation of 13 months, the 3-year overall survival rate and relapse incidence were 55% and 32%, respectively. In univariate analysis, the main parameters that negatively affected post-transplantation outcomes were older age (>55 years), a diagnosis at transplant of acute myeloid leukemia and the use of an unrelated donor. The overall 3-year cumulative incidence of non-relapse mortality was 28%, but was significantly higher in older patients than in younger ones (>55 years, 35% versus 20%, P=0.032), in those transplanted from an unrelated donor rather than a related donor (34% versus 18%, P=0.034) and in patients with a diagnosis of acute myeloid leukemia compared to myelofibrosis (29% versus 27%, P=0.045). This large retrospective study confirms that transplantation is potentially curative for patients with end-stage polycythemia vera/essential thrombocythemia progressing to myelofibrosis or acute myeloid leukemia. Relapse and non-relapse mortality remain unsolved problems for which innovative treatment approaches need to be assessed.
Predictive models may help in determining the risk/benefit ratio of allogeneic hematopoietic stem cell transplantation (HSCT) in acute leukemia (AL). Using a machine‐learning algorithm we have ...previously developed the AL‐ European Society for Blood and Marrow Transplantation (EBMT) score for prediction of mortality following transplantation. We report here the first external validation of the AL‐EBMT score in a cohort of AL patients from the Italian national transplantation network. A total of 1848 patients transplanted between the years 2000‐2014 were analyzed. The median age was 45.9. Indications for HSCT were Acute Myeloid Leukemia (68.1%) and Acute Lymphoblastic Leukemia (31.9%). The majority of patients were in first complete remission (60.4%), and received myeloablative conditioning (81.3%). Median follow‐up was 2 years. The score was well‐calibrated for prediction of day 100 mortality and 2‐year overall survival (OS), leukemia free survival (LFS), and nonrelapse related mortality, with corresponding area under the receiver‐operator curves of 0.698, 0.651, 0.653, and 0.651, respectively. Increasing score intervals were associated with a decreasing probability of 2‐year OS and LFS. The highest scoring group was associated with a hazard ratio of 3.16, 2.8, and 2.27 for 2‐year OS, LFS, and NRM, respectively. In conclusion, the AL‐EBMT score identified three distinct risk groups and was predictive of OS. It is a valid tool for stratifying the risk of acute leukemia patients undergoing allogeneic HSCT.
Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and ...cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).
An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic ...leukemia (Ph- ALL) and compared with a published control series. Following induction-consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17-67), 140/161 with Ph- ALL achieved complete remission (86.9%; 91.6% ≤55 years, P = 0.0002), with complete MRD clearing in 68/109; 55 patients were assigned to maintenance chemotherapy, and 85 to HCT due to very high-risk characteristics (hyperleukocytosis, adverse genetics, early/mature T-precursor ALL, and MRD persistence). The 5-year relapse incidence was 36%, and the treatment-related mortality rate was 18%. Median overall and relapse-free survival were 7.4 and 6.2 years, with rates of 54 and 53% at 5 years, respectively, which were significantly better than those obtained with the historical protocol (P = 0.001 and P = 0.005, respectively), without significant differences between maintenance and HCT cohorts. In prognostic analysis, MRD negativity and age ≤55 years were the most favorable independent prognostic factors. A reduction in treatment toxicity and further improvements in the risk definitions and risk-oriented design are the focuses of this ongoing research.
We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell ...transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6–73.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55–3,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or ≥4 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III–IV graft versus host disease (GVHD) (3%), grade III–IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32–1,390) from the first DLI. With a median follow-up of 461 days (2–3,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation.
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