Assessing the efficacy of allogeneic hematopoietic stem cells transplantation (allo‐HSCT) by analyzing survival end points in defined groups of acute myeloid leukemia patients: A retrospective,multicenter Polish Adult Leukemia Group study

The importance of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) for survival outcomes in patients with acute myeloid leukemia (AML) currently remains unclear. The study aimed to compare measures of clinical treatment for patients with AML in CR1 (the first complete remission) with or without being subjected to allo‐HSCT. These consisted of leukemia‐free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non‐relapse mortality disease (NRM). Subjects were 622 patients, median age of 44, forming part of the prospective, randomized, and multicenter clinical Polish Adult Leukemia Group trials during 1999–2008. The Mantel–Byar approach was used to assess allo‐HSCT on survival endpoints, accounting for a changing transplant status. Undergoing allo‐HSCT significantly improved the LFS and OS for the entire group of patients with AML in CR1, along with the DAC induction subgroup and for the group with unfavorable cytogenetics aged 41–60. The CIR demonstrated that allo‐HSCT reduced the risk of relapse for patients with AML in CR1 and those with an unfavorable cytogenetic risk. In addition, the NRM analysis showed that allo‐HSCT significantly reduced the risk of death unrelated to relapse for the entire group of AML patients in CR1 and aged 41–60. The allo‐HSCT treatment particularly benefitted survival for the AML in CR1 group having an unfavorable cytogenetic prognosis. Am. J. Hematol. 90:904–909, 2015. © 2015 Wiley Periodicals, Inc.     

Reduced intensity conditioned allograft yields favorable survival for older adults with B‐cell acute lymphoblastic leukemia

Older adults with B‐cell acute lymphoblastic leukemia (B‐ALL) have poor survival. We examined the effectiveness of reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) in adults with B‐ALL age 55 years and older and explored prognostic factors associated with long‐term outcomes. Using CIBMTR registry data, we evaluated 273 patients (median age 61, range 55–72) with B‐ALL with disease status in CR1 (71%), >CR2 (17%) and Primary Induction Failure (PIF)/Relapse (11%), who underwent RIC HCT between 2001 and 2012 using mostly unrelated donor (59%) or HLA‐matched sibling (32%). Among patients with available cytogenetic data, the Philadelphia chromosome (Ph+) was present in 50%. The 3‐year cumulative incidences of nonrelapse mortality (NRM) and relapse were 25% (95% confidence intervals (CI): 20–31%) and 47% (95% CI: 41–53%), respectively. Three‐year overall survival (OS) was 38% (95% CI: 33–44%). Relapse remained the leading cause of death accounting for 49% of all deaths. In univariate analysis, 3 year risk of NRM was significantly higher with reduced Karnofsky performance status (KPS <90: 34% (95% CI: 25–43%) versus KPS ≥90 (18%; 95% CI: 12–24%, P = 0.006). Mortality was increased in older adults (66+ vs. 55–60: Relative Risk [RR] 1.51 95% CI: 1.00–2.29, P = 0.05) and those with advanced disease (RR 2.13; 95% CI: 1.36–3.34, P = 0.001). Survival of patients in CR1 yields 45% (95% CI: 38–52%) at 3 years and no relapse occurred after 2 years. We report promising OS and acceptable NRM using RIC HCT in older patients with B‐ALL. Disease status in CR1 and good performance status are associated with improved outcomes. Am. J. Hematol. 92:42–49, 2017. © 2016 Wiley Periodicals, Inc.     

Measurable residual disease,conditioning regimen intensity,and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation

Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre‐allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged <50 years (y) or ≥50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were >18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000‐2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non‐myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non‐relapse mortality (NRM), chronic graft‐vs‐host (cGVHD), and GVHD‐free and relapse‐free survival (GRFS). The 2292 eligible patients were categorized into four paired groups: <50y MRD POS MAC (N = 240) vs RIC/NMA (N = 58); <50y MRD NEG MAC (N = 665) vs RIC/NMA (N = 195); ≥50y MRD POS MAC (N = 126) vs RIC/NMA (N = 230), and ≥50y MRD NEG MAC (N = 223) vs RIC/NMA (N = 555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the <50y MRD POS group, with worse RI (HR 1.71) and LFS (HR 1.554). Patients <50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged <50y with AML CR1 MRD POS status should preferentially be offered MAC allo‐HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for ≥50y AML CR1 MRD POS.     

A complex case of ibrutinib treatment for a CLL patient on haemodialysis

Hypoalbuminaemia has been previously described to predict worse non‐relapse mortality (NRM) and inferior overall survival (OS) in allogeneic haematopoietic cell transplant (allo‐HCT) recipients. Here, we evaluate the role of hypoalbuminaemia (<35 g/l) at time of onset of acute graft‐versus‐host disease (aGVHD) when incorporated into the refined aGVHD score. The study population consisted of 522 patients, median age 53 (18–75) years, who underwent an allo‐HCT mostly for haematological malignancies. Standard risk (SR) aGVHD comprised 467 patients (89%) and the number of high risk (HR) cases was 55 (11%). Median follow‐up for all surviving patients was 26 (3–55) months. Two‐year OS was significantly better in patients with SR aGVHD with a serum albumin ≥35 g/l compared to SR with albumin <35 g/l [70% (95% CI = 64–76%) vs. 49% (95% CI = 42–56%), P < 0·0001]. Also, patients with SR aGVHD and a serum albumin level of ≥35 g/l had a significantly lower NRM at 1‐year post‐transplantation [6% (95% CI = 3–10%) vs. 25% (95% CI = 20–32%), P < 0·0001]. After our findings are validated in a large cohort of patients, we propose that hypoalbuminaemia should be incorporated into the refined aGVHD risk score to further its ability to predict outcomes within this group.     

Allogeneic transplantation is not superior to chemotherapy in most patients over 40 years of age with Philadelphia‐negative acute lymphoblastic leukemia in first remission

Survival of patients ≥40 years of age with Philadelphia‐negative acute lymphoblastic leukemia (ALL) remains poor with current therapeutic approaches. It is unknown whether allogeneic hematopoietic stem‐cell transplantation (HSCT) in first remission confers a survival benefit compared to a chemotherapy‐only approach. We retrospectively compared the outcome of patients >40 years treated with HSCT or chemotherapy alone in first remission (n = 40 in each cohort). Three‐year overall survival (OS) and disease‐free survival (DFS) were not significantly different between the chemotherapy‐only and HSCT groups (OS, 46% [31–68] vs. 40% [27–59], P = 0.35; DFS, 31% [18–52] vs. 40% [27–59], P = 0.98). The 3‐year cumulative incidence of relapse (CIR) and non‐relapse mortality (NRM) were 61% [41–76] and 9% [2–21] for the chemotherapy‐only group and 28% [15–43] and 32% [17–47] for the transplant group (CIR, P = 0.011; NRM, P = 0.014). Allogeneic transplantation for patients ≥40 years with Ph‐negative ALL in first remission is associated with a lower CIR, but this benefit is offset by considerable NRM as compared with chemotherapy‐only approach. HSCT may be beneficial in patients with high‐risk disease features. Am. J. Hematol. 91:793–799, 2016. © 2016 Wiley Periodicals, Inc.     

Mild chronic graft‐versus‐host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study

Internal tandem duplication (ITD) of the FLT3 gene (Fms‐like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3‐ITD at diagnosis was retrospectively estimated for allo‐HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo‐HSCT after myeloablative conditioning in first complete remission of AML. FLT3‐ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo‐HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3‐ITD positive than FLT3‐ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft‐versus‐host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3‐ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo‐HSCT. It appears that allo‐HSCT does not cure patients with FLT3‐ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI.     

Comparison of non-myeloablative and reduced-intensity allogeneic stem cell transplantation in older patients with myelodysplastic syndromes

Allogeneic stem cell transplantation (HSCT) remains the only curative treatment for myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. The introduction of reduced intensity (RIC) and non-myeloablative (NMA) conditioning enabled HSCT in older or comorbid individuals representing the majority of patients. Studies comparing RIC and NMA conditioning are limited. We retrospectively analyzed 151 MDS or MDS/MPN patients older than 50 years who received NMA- or RIC-HSCT. Patients younger or older than 65 years at HSCT were analyzed separately. Patients receiving RIC-HSCT or NMA-HSCT were balanced in factors reflecting disease aggressiveness and the HCT-CI comorbidity score. The NMA conditioned patients had a higher incidence of graft rejection and chronic graft-vs-host disease. Cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and overall survival (OS), did not differ significantly with regard to the conditioning regime in the whole cohort. In patients <65 years at HSCT, NMA conditioning associated with higher NRM and shorter OS by trend, while CIR was similar in both groups. In multivariable analyzes, the conditioning regimen remained a prognostic factor for NRM and OS in patients <65 years at HSCT. In MDS patients NMA and RIC conditioning result in similar disease control, but especially patients <65 years may benefit from RIC-HSCT.     

Outcome of conditioning intensity in acute myeloid leukemia with monosomal karyotype in patients over 45 year‐old: A study from the acute leukemia working party (ALWP) of the European group of blood and marrow transplantation (EBMT)

Acute myeloid leukemia with monosomal karyotype (MK AML) carries a very poor prognosis, even after allogeneic stem cell transplantation (SCT). However, SCT remains the only curative option in this high‐risk population. Because myeloablative conditioning regimen (MAC) is associated with less relapse, we hypothesized that more intensive conditioning regimen might be beneficial for MK AML patients. We reviewed 303 patients over age 45 diagnosed with either de novo or secondary MK AML. One hundred and five patients received a MAC and 198 a reduced‐intensity conditioning (RIC). The median age at SCT was 57‐year‐old, significantly lower in the MAC (53‐year‐old) than in the RIC group (59‐year‐old). The median follow‐up was 42 months (range, 3 ? 156 months). The 3‐year overall survival (OS), leukemia‐free survival (LFS), and relapse rate (RR) were not significantly different between both groups with overall values of 34%, 29%, and 51%, respectively. On the contrary, the 3‐year nonrelapse mortality (NRM) was significantly higher in MAC recipients (28%) compared with RIC patients (16%, P = 0.004). The incidence of Grades II to IV acute graft‐versus‐host disease (GvHD) was significantly higher after a MAC (30.5%) than after a RIC (19.3%, P = 0.02). That of chronic GvHD was comparable between both groups (35%) and did not impact on LFS. Interestingly, within our MK AML cohort, hypodiploidy was significantly associated with worse outcomes. Due to reduced toxicity and comparable OS, LFS, and RR, RIC appears as a good transplant option in the very high‐risk population, including older patients, diagnosed with MK AML. Am. J. Hematol. 90:719–724, 2015. © 2015 Wiley Periodicals, Inc.     

Outcomes of elderly de novo acute myeloid leukemia treated by a risk‐adapted approach based on age,comorbidity, and performance status

Several criteria to define fitness for induction chemotherapy in elderly acute myeloid leukemia (AML) have been proposed; however, no studies have reported outcomes according to the application of a risk‐adapted approach. We treated 256 consecutive patients with elderly AML (≥60 years) with a risk‐adapted approach based on age, comorbidity score (CS), and performance status (ECOG). Eighty‐five low‐risk patients (age ≤ 65 years and ECOG 0–1 with CS < 2), 86 intermediate‐risk patients (age > 65 years or ECOG = 2 with CS < 2), and 85 high‐risk patients (ECOG > 2 or CS ≥ 2) were treated with induction chemotherapies, including standard intensive regimens, abbreviated‐scheduled regimens, and modified low‐dose cytarabine with oral etoposide (mLDAC), respectively. Overall response rates (ORR; complete response and complete response with incomplete recovery) for these three groups were 71.8%, 60.5%, and 41.2%, respectively, without a significant difference in early death rate (17.6%, 25.6%, 23.5%, P = 0.415). Among three abbreviated‐scheduled regimens, a gemtuzumab ozogamicin (GO)‐containing regimen (n = 43) showed a similar ORR rate (72.1%) to the intensive regimen. After achieving remission, 142 patients went on postremission treatments, including reduced‐intensity allogeneic transplantation (RIC, n = 41), standard consolidation (n = 71), and repeated mLDAC (n = 30) according to donor availability, age, ECOG, and CS. Multivariate analyses revealed that not only RIC, but also repeated mLDAC, resulted in significantly superior survival outcomes to standard consolidation independent of age, ECOG, and CS. Clinical benefits of mLDAC for high‐risk patients and abbreviated induction with GO for intermediate‐risk patients should be confirmed with further studies. Our results also suggest that RIC should be actively considered in elderly AML as a postremission treatment. Am. J. Hematol. 88:1074–1081, 2013. © 2013 Wiley Periodicals, Inc.     

Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of patients with mixed‐lineage‐leukemia‐rearranged acute leukemia: Results from a prospective,multi‐center study

The purpose of this study is to define the role for allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in mixed‐lineage‐leukemia (MLL)‐rearranged acute leukemia, which is now poorly understood. A prospective, multi‐center cohort study to determine whether allo‐HSCT could decrease relapse rates and improve long‐term survival of MLL+ leukemia patients was performed. Fifty‐six consecutive patients diagnosed with MLL–rearranged acute leukemia undergoing allo‐HSCT from two transplant centers in China were enrolled between October 2007 and October 2012. The trial was registered at www.chictr.org as # ChiCTR‐ONC‐12002739. The incidences of grades II to IV acute graft versus host disease (aGVHD) and of grades III and IV aGVHD were 28.8% (CI, 16.87–40.8%), and 14.2% (CI, 5.4–23.0%), respectively. The cumulative incidences for chronic GVHD (cGVHD) at 2 years after HSCT were 35.2% (CI, 21.2–49.2%). Up to April 30, 2013, 12 patients had relapsed and 11 died from relapse, and 37 patients were still alive without disease recurrence. The relapse and NRM rates at 3 years were 25.3% (CI, 12.7–37.9%) and 18.0% (CI, 2.6–33.4%), respectively. The probalities of overall survival and leukemia free survival were 61.8% (CI, 46.0–77.6%) and 56.3% (CI, 38.1–74.5%) at 3 years, respectively. Patients transplanted during their hematological first complete remission (CR1) had a lower relapse rate (17.9% vs. 48.1%, P = 0.03) compared with patients transplanted beyond CR1. The median overall survival for the 29 patients not receiving allo‐HSCT during the study period was 145 days from diagnosis. This study showed that allo‐HSCT could be a valuable treatment choice for MLL+ acute leukemia. Am. J. Hematol. 89:130–136, 2014. © 2013 Wiley Periodicals, Inc.     

Retrospective study of allogeneic haematopoietic stem-cell transplantation for myelofibrosis

Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We retrospectively analyzed the outcome of patients who underwent allogeneic HSCT, 1994-2008, and the potential risk factors affecting non-relapse mortality (NRM), OS and relapse-free survival (RFS). A total of 39 patients, 15-65 (median 49) years old, diagnosed with primary (n=27) or secondary (n=12) myelofibrosis underwent HSCT (25 related and 14 unrelated). In ten patients, disease had transformed into acute leukaemia. Lille prognosis score was low for 9, intermediate for 16 and high for 14 patients. The conditioning regimen was myeloablative (MAC) for 15 and reduced-intensity (RIC) fludarabine-based for 24, with successful engraftment in 38 patients. A total of 31 patients developed grade I-IV GvHD; 19 developed chronic GvHD. The 3-year OS, RFS and NRM rates (95% confidence interval) were 60% (42-74), 54% (37-59) and 30% (30-45), respectively.     

Role of autologous hematopoietic stem cell transplantation according to the NPM1/FLT3‐ITD molecular status for cytogenetically normal AML patients: A GOELAMS study

The choice of postremission therapy for acute myeloid leukemia (AML) patients is now based on the blasts' cytogenetic and molecular profile. However, the potential benefit of autologous hematopoietic stem cell transplantation (auto‐HSCT) according to the NPM1/FLT3‐ITD status has been poorly studied in AML patients with a normal karyotype (NK). Therefore, we evaluated the NPM1/FLT3‐ITD molecular status in 135 NK‐AML patients treated by allogeneic HSCT (allo‐HSCT), auto‐HSCT, or chemotherapy as consolidation therapy within the GOELAMS LAM‐2001 trial. In univariate analyzes, 4‐year leukemia‐free survival (LFS) and overall survival (OS) were significantly higher for NPM1+/FLT3‐ITD? patients compared with patients presenting another molecular profile (61 vs. 43% and 72 vs. 48%, P = 0.02 and P = 0.01, respectively). In the NPM1+/FLT3‐ITD? subgroup, there was no benefit for allo‐HSCT or auto‐HSCT vs. chemotherapy (4‐year LFS: 71, 56, and 60%; 4‐year OS: 73, 71, and 60%, respectively; P = NS). For patients with other NPM1/FLT3‐ITD molecular profiles, allo‐HSCT was found to be the best consolidation therapy, whereas auto‐HSCT was associated with a better outcome when compared with chemotherapy (allo‐HSCT‐, auto‐HSCT‐, and chemotherapy‐related 4‐year LFS: 68, 44, and 36%, P = 0.004; 4‐year OS: 68, 52, and 29%, respectively, P = 0.02). Our study indicates that allo‐HSCT and auto‐HSCT provide similar outcomes compared with chemotherapy as consolidation for NPM1+/FLT3‐ITD? NK‐AML patients. For NK‐AML patients with an adverse molecular profile, auto‐HSCT could represent an alternative therapeutic approach when no human leukocyte antigen–matched allogeneic donor is available. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.     

The hematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) is an outcome predictor for partially matched related donor transplantation

To validate the predictive ability of the Hematopoietic Cell Transplantation‐Specific Comorbidity Index (HCT‐CI) on the outcome of hematopoietic stem cell transplantation (HSCT) patients who received transplants from partially matched related donors (PMRD), a total of 526 patients who received PMRD HSCT between January 2006 and December 2009 at the Institute of Hematology, Peking University were enrolled. Patients were grouped according to their HCT‐CI score; 31.0%, 31.4%, and 37.6% of patients had HCT‐CI scores of 0, 1–2, and ≥3, respectively. Patients with HCT‐CI scores of ≥3 had a significantly poorer 2‐year overall survival (OS) than patients with HCT‐CI scores of 0–2 (54.55% vs. 78.05%, P < 0.001). In addition, patients with HCT‐CI scores of ≥3 had a significantly higher 2‐year cumulative incidence of relapse and nonrelapse mortality (NRM) than patients with scores of 0–2 (relapse: 23.23% vs. 11.59%, P < 0.001; NRM: 34.30% vs. 15.93%, P < 0.001). HCT‐CI scores of <3 were associated with better OS, less relapse, and lower NRM in multivariate analysis. Patients who had high comorbidity scores as well as high‐risk disease had the poorest outcomes. Therefore, we found that HCT‐CI is associated with the outcomes of PMRD HSCT and we should closely monitor patients with a high comorbidity burden. Am. J. Hematol. 88:497–502, 2013. © 2013 Wiley Periodicals, Inc.     

Mobilized peripheral blood stem cells compared with bone marrow from HLA-identical siblings for reduced-intensity conditioning transplantation in acute myeloid leukemia in complete remission: a retrospective analysis from the Acute Leukemia Working Party of EBMT

Reduced‐intensity conditioning (RIC)‐alloSCT is increasingly used for acute myelogenous leukemia. Limited data are available for the comparison of peripheral blood stem cells with bone marrow for RIC‐alloSCT. We used the European Group for Blood and Marrow Transplantation (EBMT) ALWP data to compare the outcome of mobilized peripheral blood stem cells (PBSC) (n = 1430) vs. bone marrow (BM) (n = 107) for acute myelogenous leukemia (AML) patients with complete remission that underwent RIC‐alloSCT from compatible sibling donors. The leukemia features, the disease status, and the time from diagnosis were similar between the two groups. Engraftment was achieved in 99% and 93% in the PBSC and BM groups, respectively (P < 0.0001). The day of engraftment was significantly earlier for the PBSC vs. the BM group, 15 (1–59) and 19 (5–69), respectively (P < 0.001). Acute GVHD, severe GVHD (grade III–IV) and chronic GVHD did not differ between the groups. leukemia‐free survival (LFS), relapse, and non‐relapsed mortality (NRM) were 51 ± 2%, 32 ± 1%, and 17 ± 1% vs. 50 ± 6%, 38 ± 6%, and 12 ± 3% for the PBSC and BM groups, respectively. Our results indicate faster engraftment, but no difference in GVHD, LFS, relapse, and NRM when comparing PBSC to BM grafts from sibling donors following RIC conditioning. This is the first study comparing PBSC to BM grafts in the RIC setting, analyzing a homogeneous population of patients with AML in remission. Whether PBSC should be preferred for advanced phases of the disease, where the outcome is dominated by relapse incidences, needs further investigation.     

Sequential systematic anti‐mold prophylaxis with micafungin and voriconazole results in very low incidence of invasive mold infections in patients undergoing allogeneic hematopoietic stem cell transplantation

Recipients of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) are at high risk for invasive mold infections (IMI). The goal of the study is to describe the incidence and outcome of IMI in patients after allo‐HSCT in a large cohort of patients receiving anti‐mold prophylaxis. We conducted a retrospective review of 988 consecutive adults who underwent allo‐HSCT in our center from 2008 through 2014. Standard prophylaxis consisted of micafungin 150 mg IV daily from admission to day +7 ± 3 followed by voriconazole until day +75 to +100. Cases meeting criteria for proven or probable IMI according to EORTC‐MSG criteria were included. Median age at HSCT was 54 years. The most common diagnoses were acute myeloid leukemia (n = 351, 36%) and lymphoid malignancies (n = 248, 25%). Matched related or unrelated donors (URD) were used in 686 (69%) patients, mismatched URD in 142 (14%) and cord blood units in 154 (16%). Twenty‐one patients were diagnosed with IMI after allo‐HSCT, 19 probable and 2 proven, and one patient was diagnosed postmortem. Microbiological diagnosis was established in 9 cases, 5 of them being Aspergillus. One‐year cumulative incidence (CI) of IMI was 1.6% (95% CI 0.9‐2.5) while 12‐week overall survival after IMI was 39% (95% CI 24‐65) Analyzed by disease, there was a trend for a higher 1‐year CI of IMI in patients with ALL (5% [95% CI 1.6‐11.4]) when compared with AML (1.4%), MDS (1.5%) and lymphoma (1.2%), P = .06. The 1‐year CI of IMI after transplantation is low in patients receiving anti‐mold prophylaxis with micafungin bridged to voriconazole, although these infections are associated with a higher risk of mortality.     

Primary treatment of leukemia relapses after allogeneic hematopoietic stem cell transplantation with reduced‐intensity conditioning second transplantation from the original donor

Acute leukemia relapsing after allogeneic hematopoietic stem cell transplantation (HSCT) has dismal outcome. Consecutive consenting patients (acute myeloid leukemia: N = 71; acute lymphoblastic leukemia: N = 37), at a median age of 37 (16–57) years, who had relapsed 7.9 (1.3–132) months post‐HSCT, were treated with three cytarabine‐based intensive regimens as reduced‐intensity conditioning (RIC), followed by infusion of mobilized HSC from the original donors. There were four treatment‐related mortalities (TRMs). Of 104 evaluable cases, 72 patients (67%) achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi). The median overall survival (OS) of the entire cohort was 11.6 months. The OS of patients achieving CR/CRi after the first RIC/HSCT was 18.8 months, as compared with 3.9 months for those not (P < 0.01). For 32 patients with nonremission, 11 received a repeat RIC‐HSCT, leading to CR/CRi in three cases. Therefore, 75/108 (69%) of patients achieved CR/CRi after one or two courses of RIC‐HSCT. Among CR/CRi patients, 48 cases relapsed again after 6.1 (1.0–64.4) months. Thirty cases received a repeat RIC‐HSCT, leading to CR/CRi in 22 patients. Multivariate analyses showed a significant impact of remission duration after initial HSCT (P = 0.026) and the presence of acute graft‐versus‐host disease after RIC‐HSCT (P = 0.011) on CR/CRi. RIC‐HSCT as primary treatment for acute leukemic relapses post‐HSCT induced a high CR rate with low TRM. Optimal postremission treatment remains to be defined. Am. J. Hematol. 88:485–491, 2013. © 2013 Wiley Periodicals, Inc.     

Allogeneic hematopoietic stem cell transplantation could improve survival of cytogenetically normal adult acute myeloid leukemia patients with DNMT3A mutations

DNMT3A mutations are frequent in cytogenetically normal acute myeloid leukemia (cn‐AML) patients and associated with poor survival. The role of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in DNMT3A^mut cn‐AML patients remains unclear. In this study, we retrospectively analyzed the prognostic impact of DNMT3A mutations and explored the role of allo‐HSCT in 308 cn‐AML patients who received consolidation of intensive chemotherapy or allo‐HSCT in our center from March 2005 to May 2014. In the whole cohort, 63 patients (20.5%) were identified with DNMT3A exon 23 mutations and R882H was the most frequent variant. DNMT3A^mut patients had shorter overall survival (3‐year OS: 31.9% vs. 52.0%, P = 0.009) and disease‐free survival (3‐year DFS: 21.8% vs. 40.1%, P = 0.004) compared with DNMT3A^wt patients. Based on FLT3/NPM1/CEBPA mutations, 308 cn‐AML patients were divided into favorable/intermediate group (n = 262) and unfavorable group (n = 46). There were no significant differences in 3‐year OS and 3‐year DFS between DNMT3A^mut and DNMT3A^wt patients in both favorable/intermediate and unfavorable groups. Additionally, in multivariate analysis, DNMT3A mutation remained an independent adverse prognostic factor for the survival. In the DNMT3A^mut cohort, 23 complete remission (CR) patients received allo‐HSCT consolidation and 32 CR patients received chemotherapy consolidation, dramatic differences were observed in 3‐year OS (51.7% vs. 28.9%, P = 0.048) and 3‐year DFS (41.6% vs. 14.9%, P = 0.024) between allo‐HSCT group and chemotherapy group. Collectively, DNMT3A mutation is a poor prognostic factor for cn‐AML patients and allo‐HSCT could improve survival of cn‐AML patients with DNMT3A mutations. Am. J. Hematol. 90:992–997, 2015. © 2015 Wiley Periodicals, Inc.     

Role of HCT-comorbidity index, age and disease status at transplantation in predicting survival and non-relapse mortality in patients with myelodysplasia and leukemia undergoing reduced-intensity-conditioning hemopoeitic progenitor cell transplantation

Reduced-intensity-conditioning (RIC) regimens have allowed older patients to have allogeneic hemopoietic progenitor cell transplantation (HCT). This retrospective study was done to assess the impact of the HCT-comorbidity index (HCT-CI) in addition to other pre-transplant factors on the outcome of RIC transplants. In all 121 such patients were transplanted between 2002 and 2008 at two centers using fludarabine, melphalan and alumtuzumab conditioning. The OS and non-relapse mortality (NRM) were 56% and 30% at 2 years, respectively. The NRM of patients with HCT-CI ≥ 3 was not significantly different from the NRM of those with HCT-CI 0-2 (P value 0.24). Age and disease status at transplantation were significant factors affecting OS (P value 0.07 and 0.008, respectively), with no impact on NRM (P value 0.14 and 0.24, respectively). Although HCT-CI on its own did not independently predict NRM or survival, taken together with age and disease status at transplantation, it can be utilized to further delineate RIC allograft recipients into groups with different outcomes. Patients with none or one of these three adverse factors (age ≥ 60 years, leukemia in second CR or PR/high-risk myelodysplasia (MDS) and HCT-CI ≥ 3) had a 2-year NRM and survival of 18% and 80%, respectively, which was significantly better than those of patients with two or more of these adverse factors with 2-year NRM and survival of 46% (P value 0.03) and 40% (P value 0.02), respectively. None of the patients with all three adverse factors (age ≥ 60 years, leukemia in second CR or PR/high-risk MDS and HCT-CI ≥ 3) had survived for 2 years (median survival 12 months). This information can be used to guide patient selection for RIC transplants and to appropriately counsel patients of the risks and benefits of this treatment.     

Prognostic impact of complex and/or monosomal karyotypes in post-transplant poor cytogenetic acute myeloid leukaemia: A quantitative approach

To evaluate the prognostic impact of complex karyotype (CK) and/or monosomal karyotype (MK) in combination with various clinical factors on allogeneic stem cell transplantation (HSCT) outcomes of patients with acute myeloid leukaemia (AML), we analysed the registry database of adult AML patients who underwent allogeneic HSCT between 2000 and 2019 in Japan. Among 16 094 patients, those with poor cytogenetic risk (N = 3345) showed poor overall survival (OS) after HSCT (25.3% at 5 years). Multivariate analyses revealed that CK and/or MK (hazard ratio [HR], 1.31 for CK without MK; 1.27 for MK without CK; and 1.73 for both), age at HSCT ≥50 years (HR, 1.58), male sex (HR, 1.40), performance status ≥2 (HR, 1.89), HCT-CI score ≥3 (HR, 1.23), non-remission status at HSCT (HR, 2.49), and time from diagnosis to HSCT ≥3 months (HR, 1.24) independently reduced post-HSCT OS among patients with poor cytogenetic risk AML. A risk scoring system based on the multivariate analysis successfully stratified patients into five distinct groups for OS. This study confirms the negative effects of CK and MK on post-HSCT outcomes, and offers a powerful risk scoring system for predicting prognoses after HSCT among AML patients with unfavourable cytogenetics.     

Comparison of umbilical cord blood allogeneic stem cell transplantation vs. auto‐SCT for adult acute myeloid leukemia patients in second complete remission at transplant: a retrospective study on behalf of the SFGM‐TC

This retrospective study considered the outcomes of 181 patients with acute myeloid leukemia (AML) transplanted in second complete remission (CR2) between January 2005 and April 2012 and who received either a myeloablative autologous stem cell transplant (Auto‐SCT; n = 82; median age: 48 years; median follow‐up: 45 months) or an umbilical cord blood (UCB) allogeneic SCT (n = 99, median age: 46 years; median follow‐up: 36 months; conditioning regimens: myeloablative n = 21, reduced n = 78; single unit n = 37, double units n = 62). Although the Auto group showed a significant better prognostic profile at transplant, with longer median interval between diagnosis and time of graft, higher incidence of good‐risk cytogenetics and lower number of previously transplanted patients, 3‐year OS and LFS were similar between both groups (Auto: 59 ± 6% vs. 50 ± 6%, P = 0.45; and 57 ± 6% vs. 46 ± 6%, P = 0.37). In multivariate analysis, UCB allo‐SCT was associated with lower relapse incidence (HR: 0.3, 95% CI: 0.11–0.82, P = 0.02), but higher non‐relapse mortality (NRM) (HR: 4.16; 95% CI: 1.46–11.9, P = 0.008). Results from this large study suggest that UCB allo‐SCT provides better disease control than auto‐SCT, which is especially important in the setting of high‐risk disease. However, this disease control advantage is counterbalanced by higher toxicity, highlighting the need for novel approaches aiming to decrease NRM after UCB allo‐SCT.