High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG.

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/m2) or Id-MTX (0.5 g/m2). 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.

A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation.

Previous studies have suggested that tacrolimus (TAC) is more potent than cyclosporine (CSA) for prophylaxis against acute GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). However, the target blood concentrations of these drugs in these studies were not consistent with the current recommendations. Therefore, we performed a randomized controlled trial to compare CSA and TAC with target blood concentrations of 500 and 15 ng/ml, respectively, to prevent acute GVHD after unrelated HSCT. A total of 107 patients were randomized into a CSA group (n=53) or a TAC group (n=54). During the first 4 weeks after HSCT, more than 90% of the patients achieved a mean blood concentration of between 80 and 120% of the target concentration. The incidences of grade II-IV and grade III-IV acute GVHD were 39.6 and 7.5% for the CSA group and 33.3 and 9.4% for the TAC group, respectively (P=0.41 and P=0.76). Other clinical outcomes, including overall survival, disease-free survival and the incidences of relapse, non-relapse mortality, and organ toxicities, were also equivalent. We concluded that the combinations of CSA and TAC with strict dose adjustment showed similar efficacies and toxicities as prophylaxis against acute GVHD after unrelated HSCT.

Early-onset acute kidney injury is a poor prognostic sign for allogeneic SCT recipients.

Acute kidney injury (AKI) following stem-cell transplantation (SCT) contributes to a poor prognosis, yet its impact may vary depending on the timing of AKI onset. A prospective cohort study was performed to understand the significance of the onset timing in 103 allogeneic SCT (allo-SCT) recipients. AKI prior to stem-cell engraftment was defined as early AKI and subsequently occurring AKI as late AKI. Propensity score (PS) for early AKI was calculated using a logistic regression model to reduce confounding effects related to differences in clinical background between the early and late AKI groups. The cumulative incidences of early and late AKI were 22.3% and 54.9%, respectively. Non-relapse mortality (NRM) was 39.1% and 7.0%, and overall survival (OS) was 56.5% and 90.9% in early and late AKI at 100 days after AKI, respectively (P<0.001). The cumulative incidence of chronic kidney disease (CKD) over 2 years after SCT was 41.5% and 19.1% in early and late AKI, respectively (P=0.048). Logistic regression analysis adjusted for the PS showed that early AKI was significantly associated with OS (odds ratio (95% confidence interval); 4.63 (1.15-21.4), P=0.031) but with neither NRM (1.25 (0.28-5.33), P=0.766) nor CKD (1.85 (0.41-8.60), P=0.422). In conclusion, early AKI may portend a poor survival for allo-SCT recipients.

Clinical features and risk factors for developing varicella zoster virus dissemination following hematopoietic stem cell transplantation.

BACKGROUND: We retrospectively analyzed 80 instances of varicella zoster virus (VZV) disease in 72 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) and examined the clinical differences between localized and disseminated disease. Risk factors for developing VZV dissemination were also evaluated. RESULTS: Of the 80 instances, 54 instances were localized diseases and 26 were disseminated diseases. Patient characteristics did not differ significantly between the 2 groups, except for the first-line therapy and the duration from symptom onset to treatment. In the disseminated group, intravenous acyclovir was used as the first-line therapy more frequently, and more time elapsed before beginning antiviral therapy compared with the localized group. In multivariate analyses, the duration from symptom onset to treatment was identified as an independent risk factor that significantly affected the development of VZV dissemination. Gender, total body irradiation, and chronic graft-versus-host disease, of which the latter 2 factors were reported as risk factors for the development of VZV disease after HSCT, did not affect the development of VZV dissemination. CONCLUSION: Our results suggest that VZV infection or reactivation may easily progress to viremia with delayed use of antiviral agents and may result in VZV dissemination in immunocompromised patients.

Pre-transplant risk factors for cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia after hematopoietic cell transplantation.

Cryptogenic organizing pneumonia (COP), previously known as bronchiolitis obliterans organizing pneumonia (BOOP), is a significant complication after allogeneic hematopoietic SCT (HCT). However, the pathogenesis of this complication has not yet been elucidated. Therefore, we identified the pre-transplant risk factors for the development of COP/BOOP using the Japan transplant registry database between 2005 and 2009. Among 9550 eligible recipients, 193 experienced COP/BOOP (2%). HLA disparity (odds ratio (OR) 1.51, P=0.05), female-to-male HCT (OR 1.53, P=0.023), and PBSC transplant (OR 1.84, P=0.0076) were significantly associated with an increased risk of COP/BOOP. On the other hand, BU-based myeloablative conditioning (OR 0.52, P=0.033), or fludarabine-based reduced-intensity conditioning (OR 0.50, P=0.0011) in comparison with a TBI-based regimen and in vivo T-cell depletion (OR 0.46, P=0.055) were associated with a lower risk. Of the 193 patients with COP/BOOP, 77 died, including non-relapse death in 46 (59%). Pulmonary failure and fatal infection accounted for 41% (n=19) and 26% (n=12) of the non-relapse death. Allogeneic immunity and conditioning toxicity could be associated with COP/BOOP. Prospective studies are required to elucidate the true risk factors for COP/BOOP and to develop a prophylactic approach.

New-onset microalbuminuria following allogeneic myeloablative SCT is a sign of near-term decrease in renal function.

The emergence of microalbuminuria following conditioning chemotherapy may predict the development of renal dysfunction. To confirm this, a 1-year retrospective cohort study was conducted in 31 myeloablative allogeneic SCT patients who received five consecutive measurements of albuminuria before conditioning therapy and on days 0, 7, 14 and 28 following SCT. The cohort had neither microalbuminuria nor renal dysfunction at baseline. Microalbuminuria was defined as an albumin-creatinine (Cr) ratio over 30 mg/g, and renal dysfunction was as an estimated glomerular filtration rate <60 mL/min per 1.73 m(2). Cumulative incidence of renal dysfunction over time was analyzed by the Kaplan-Meier method. Multivariate Cox proportional hazards analysis was used to examine an association of de novo microalbuminuria with the incidence of renal dysfunction. In all, 16 patients (52%) developed microalbuminuria that was positive at least two times among the four measurements after SCT. The actuarial occurrence of chronic kidney disease was significantly higher in patients who developed microalbuminuria than in those who did not. Incidence of microalbuminuria had a significant risk of subsequent renal dysfunction (hazard ratio (95% confidence interval), 7.3 (1.2-140)). In conclusion, de novo microalbuminuria following conditioning therapy is a warning of near-term loss of renal function.

Allogeneic hematopoietic stem cell transplantation for intermediate cytogenetic risk AML in first CR.

Allogeneic hematopoietic SCT (allo-HCT) from matched sibling donor (MSD) is recommended for younger patients with intermediate cytogenetic risk AML in first CR (CR1), whereas the role of alternative donor transplants in these patients is unknown. We retrospectively analyzed 605 patients with intermediate-risk AML, who received myeloablative allo-HCT in CR1. The 4-year OS for MSD (n=290) and matched unrelated donor (MUD; n=141) was 65% and 68% (P=0.50), respectively. In multivariate analysis, MUD had a similar risk of overall mortality as MSD (hazard ratio=0.90; 95% confidence interval, 0.62-1.30; P=0.58), whereas older age, female donor/male recipient (FDMR) combination, and requiring more than one course of induction chemotherapy to achieve CR1 were poor prognostic factors for OS. Thus, OS after MUD HCT with sex combinations other than FDMR was significantly higher than that after MSD HCT from female donors to male recipients (4-year OS 72% versus 55%, P=0.04). These results suggest that HCT, not only from MSD, but also from MUD, should be considered in younger patients with intermediate-risk AML in CR1, and that the donor-recipient sex combination is more important than the donor type in donor selection.

The significant impact of acute kidney injury on CKD in patients who survived over 10 years after myeloablative allogeneic SCT.

There are no well-defined studies of chronic kidney disease (CKD) among long-term survivors after hematopoietic SCT. A retrospective longitudinal study was conducted to characterize CKD in 77 subjects that had undergone myeloablative allogeneic SCT, all of whom had their serum creatinine (Cr) levels followed-up during the 10-year period after SCT. Their mean (range) survival time was 14.4 (10.5-20.2) years. CKD was defined as a persistent decrease in the Cr-based estimated glomerular filtration rate to below 60 mL/min/1.73 m². Acute kidney injury (AKI) was defined as an increase in Cr within the first 100 days after SCT, and its severity was classified into three stages according to the AKIN criteria. Kaplan-Meier and Cox proportional hazards regression analyses evaluated the association between AKI and the incidence of CKD. The cumulative incidence of CKD increased over time and reached 34% at 10 years. After adjusting for known risks for post-SCT CKD, each AKIN stage was strongly associated with the incidence of CKD. The incidence of CKD probably increases over time among subjects who are alive at >10 years after SCT. This study places a new emphasis on AKI as an important risk factor for CKD in post-SCT subjects.

Anti-host isohemagglutinin production is associated with a higher risk of acute GVHD in ABO-incompatible transplantation.

We retrospectively analyzed the association between anti-host isohemagglutinin (IH) production and the development of acute GVHD. Of 189 patients who received minor or major/minor ABO-incompatible hematopoietic SCT (HSCT) at our hospital, 36 patients (19%) showed IH production. IH was detected before the onset of acute GVHD in 10, around the same time in 8, and after the onset of acute GVHD in 17 patients. The cumulative incidence of grade II-IV acute GVHD was significantly higher in the IH+ group compared with the IH- group (P<0.0001). The higher risk of acute GVHD that was associated with IH production occurred irrespective of human leukocyte Ag compatibility and donor type. Furthermore, the incidence of acute GVHD in the IH- group was comparable to that seen in major ABO-incompatible or -compatible HSCT. Our findings not only showed a strong association between IH production and acute GVHD development, but also suggested that IH production might be a useful predictor of subsequent acute GVHD after ABO-incompatible HSCT.

Mortality and medical morbidity beyond 2 years after allogeneic hematopoietic stem cell transplantation: experience at a single institution.

Long-term follow-up data on patients who underwent allogeneic hematopoietic stem cell transplantation in our institution between 1990 and 2007 were evaluated for mortality and morbidity beyond 2 years post-transplantation. Follow-up data were obtained annually from medical records or by mail to the relevant hospitals, or to the patients themselves. In total, 369 patients survived more than 2 years, but 72 patients died thereafter. Relapse was the most common cause of death, followed by pulmonary complications and infections. Second malignancy was the cause of death in seven patients. Chronic kidney disease was one of the most serious complications, and seven patients needed regular dialysis or kidney transplantation. Hypertension and diabetes were reported in 19 and 11.2% patients, respectively. Second malignancies were observed in 14 patients beyond 2 years after transplantation, and the oral mucosa, tongue, esophagus and colon were the main organs involved. We recommend that physicians caring for allogeneic hematopoietic stem cell transplant patients should at a minimum examine kidney function and gastrointestinal tract for secondary malignancy, in addition to hematological status. Such information will be useful for optimizing outcomes through the detection and prevention of complications.

Glycogen synthase kinase-3beta and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells.

Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes cyclin D2 by inhibition of glycogen synthase kinase-3beta (GSK3beta) through Janus kinase2-dependent activation of phosphatidylinositol 3'-kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of cyclin D2, which was mediated by activation of p38. GSK3beta and p38 was demonstrated to phosphorylate cyclin D2 on Thr280 in vitro, while a cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of cyclin D2 in primary leukemic or myeloma cells. These results indicate that cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3beta or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.