High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL ...has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m
) or Id-MTX (0.5 g/m
). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.
The effect of graft-versus-host disease (GVHD) on transplant outcomes after unrelated cord blood transplantation (UCBT) has not been fully elucidated. We analyzed the impact of acute and chronic GVHD ...on outcomes in adult patients with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n=2558). The effect of GVHD on outcomes was analyzed after adjusting for other significant variables. The occurrence of GVHD was treated as a time-dependent covariate. The occurrence of grade 1-2 or 3-4 acute GVHD was significantly associated with a lower relapse rate. Grade 3-4 acute GVHD was associated with a higher risk of non-relapse and overall mortality than no acute GVHD, whereas grade 1-2 acute GVHD was associated with a lower risk of non-relapse and overall mortality than no acute GVHD. Limited or extensive chronic GVHD was significantly associated with a lower relapse rate. Limited chronic GVHD was associated with a lower overall and non-relapse mortality than no chronic GVHD. In conclusion, mild acute or chronic GVHD was associated not only with a low risk of relapse but also with a low risk of non-relapse mortality, and provides a survival benefit in UCBT.
To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations ...in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.
HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. We retrospectively analyzed ...3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD (n=2089) and 1MMUD with antithymocyte globulin (ATG) (1MM-ATG(+); n=109) with those of 1MMUD without ATG (1MM-ATG(-); n=1115). The median total dose of ATG (thymoglobulin) was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MM-ATG(+) group. The rates of grade III-IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM-ATG(-) group (hazard ratio (HR) 0.77, P=0.016; HR 0.74; P<0.001; and HR 0.87, P=0.020, respectively). Likewise, the rates of grade III-IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(-) group (HR 0.42, P=0.035; HR 0.35, P<0.001; and HR 0.71, P=0.042, respectively). The outcome of allo-HCT from 1MM-ATG(-) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse.
A nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin at a median total dose of 2.5 mg/kg (range, 0.5-18.5 mg/kg) as a second-line treatment for ...steroid-resistant acute GvHD was conducted. Of the 92 evaluable patients, improvement (complete or partial response) was observed in 55 patients (60%). Multivariate analysis demonstrated that male sex and grade III and IV acute GvHD were associated with a lower improvement rate, whereas thymoglobulin dose (<2.0, 2.0-3.9 and ⩾4.0 mg/kg) was NS. Factors associated with significantly higher nonrelapse mortality included higher patient age (⩾50 years), grade IV acute GvHD, no improvement of GvHD and higher dose of thymoglobulin (hazard ratio, 2.55; 95% confidence interval, 1.34-4.85; P=0.004 for 2.0-3.9 mg/kg group and 1.79; 0.91-3.55; P=0.093 for ⩾4.0 mg/kg group). Higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Taken together, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously, and <2.0 mg/kg thymoglobulin is recommended in terms of the balance between efficacy and adverse effects.
Abstract To assess the safety and efficacy of allogeneic stem cell transplantation from haploidentical related donors (haplo-SCT) as 2nd transplantation for patients with early relapsed disease, we ...retrospectively evaluated 7 consecutive patients (median age, 42 years; range, 29–63 years) who experienced relapse within 1 year of the 1st transplantation and received haplo-SCT as a 2nd transplantation. Among the 7 patients who received haplo-SCT, 2 who were in morphologically complete remission (CR) at transplantation were conditioned with a reduced-intensity regimen, and the 5 non-CR patients were conditioned with a myeloablative regimen. Both conditioning regimens included antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone. Sustained neutrophil engraftment was achieved in all 7 patients. One patient developed severe acute GVHD. Notably, only 1 patient experienced relapse, and each patient achieved longer CR duration than after the 1st transplantation. Three of the 7 patients died from treatment-related causes: acute GVHD, post-transplantation lymphoproliferative disorder, and bacterial pneumonia. At the time of analysis, the 2-year overall survival rate of these 7 patients was 42.9%. This suggests that use of haploidentical related donors is a viable alternative for 2nd transplantation and should be confirmed in larger cohorts.
Preemptive therapy is the standard strategy for preventing CMV disease after allogeneic hematopoietic SCT. In this study, unrelated BMT recipients were randomly assigned to a plasma real-time PCR ...group or an antigenemia group to compare the value of these monitoring tools for CMV reactivation. Ganciclovir (GCV) was started at 5 mg/kg/day when PCR reached 300 copies per ml or when antigenemia reached three positive cells per two slides. A total of 88 patients were randomized into the antigenemia group (n=45) or the PCR group (n=43). A significantly higher number of patients reached the threshold in the antigenemia group than in the PCR group (73.3 vs 44.2%, P=0.0089). However, only three patients (one in the antigenemia group and two in the PCR group) developed early CMV disease. These patients exclusively had colitis and were successfully treated with GCV or foscarnet. The median number of antigenemia-positive cells at the start of GCV was 47 in the PCR group. These findings suggest that antigenemia assay with the current cutoff was too sensitive and led to unnecessary use of GCV. However, the appropriateness of the threshold may be different by the methodology used, and therefore, it is difficult to generalize.
This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or ...myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (<1000 ng/mL) and high-ferritin group (⩾1000 ng/mL). The primary end point was the cumulative incidence of infection within 100 days after HSCT, which was similar between the two groups: bloodstream infection, 35 vs 38%, P=0.65; bacterial infection, 44 vs 41%, P=0.68; and fungal infection, 6 vs 8%, P=0.71. The 1-year adjusted probability of OS of the high-ferritin group was significantly lower than that of the low-ferritin group (76 vs 63%, P=0.017). Using receiver operating characteristic curve, the threshold of pretransplant serum ferritin levels for bloodstream infection was 1400 ng/mL; the threshold for OS, EFS and non-relapse mortality was 1349 ng/mL. In conclusion, pretransplant serum ferritin levels of ⩾1000 ng/mL did not influence the incidence of infection but adversely affected OS after HSCT. A higher threshold of pretransplant serum ferritin levels may predict HSCT outcomes.
The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U ...protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.
We retrospectively investigated air-leak syndrome (ALS), including pneumothorax and mediastinal/s.c. emphysema, following allogeneic hematopoietic SCT. Eighteen patients (1.2%) developed ALS among ...1515 undergoing SCT between 1994 and 2005 at the nine hospitals participating in the Kanto Study Group on Cell Therapy. The median onset of ALS was at 575 days (range: 105-1766) after SCT and 14 patients (77.8%) had experienced late onset noninfectious pulmonary complications (LONIPC) before ALS. Chronic GVHD (cGVHD) was the strongest risk factor for ALS (odds ratio 13.5, P=0.013 by multivariate analysis). Repeat SCT, male sex and age <38 years at the time of transplantation were also significant risk factors for ALS. Patients with ALS had a significantly worse survival rate than those without ALS (61.5 vs 14.9% at 3 years; P=0.000). The main cause of death was respiratory complications in 8 of the 18 patients. In conclusion, ALS is a rare complication of SCT that is more likely to occur in relatively young male patients with cGVHD and/or LONIPC. It is possible that better understanding and treatment of LONIPC may lead to prevention of ALS.
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