Retrospective Study of Incidence and Prognostic Significance of Eosinophilia after Allogeneic Hematopoietic Stem Cell Transplantation: Influence of Corticosteroid Therapy.

OBJECTIVE: The clinical significance of eosinophilia after allogeneic hematopoietic stem cell transplantation is controversial. This study aimed to retrospectively study the impact of eosinophilia on the outcome of allogeneic hematopoietic stem cell transplantation by taking into account the influence of corticosteroid therapy. MATERIALS AND METHODS: We retrospectively studied 204 patients with acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplantation from January 2001 to December 2010. RESULTS: The median age was 43 years (minimum-maximum: 17-65 years). Myeloablative conditioning was used in 153 patients and reduced intensity conditioning was employed in 51 patients. Donor cells were from bone marrow in 132 patients, peripheral blood in 34, and cord blood in 38. Eosinophilia was detected in 71 patients and there was no significant predictor of eosinophilia by multivariate analysis. There was no relationship between occurrence of eosinophilia and the incidence or grade of acute graft-versus-host disease when the patients were stratified according to corticosteroid treatment. Although eosinophilia was a prognostic factor for 5-year overall survival by univariate analysis, it was not a significant indicator by multivariate analysis. CONCLUSION: These results suggest that the clinical significance of eosinophilia in patients receiving allogeneic hematopoietic stem cell transplantation should be assessed with consideration of systemic corticosteroid administration.

Clinical significance of the administration of cytarabine or thiotepa in addition to total body irradiation and cyclophosphamide for allogeneic hematopoietic cell transplantation in patients with acute leukemia.

A multicenter retrospective study was performed to determine the significance of adding cytarabine (CA) or thiotepa (TT) in the context of total body irradiation (TBI) and cyclophosphamide (CY). A total of 322 patients who underwent allogeneic hematopoietic cell transplantation (HCT) were distributed to the following three groups: TBI/CY (n = 75), TBI/CY/CA (n = 77), and TBI/CY/TT (n = 170). In the TBI/CY/TT group, 164 of patients (96 %) received HCT during the previous year (2000-2005). Multivariate analysis revealed that the TBI/CY/TT group demonstrated a trend of poorer survival rate than the TBI/CY group, [hazard ratio (HR) = 1.49, 95 % confidence interval (CI) 0.99-2.24, P = 0.055] with a higher non-relapse mortality (NRM) (HR = 2.34, 95 % CI 1.35-4.06, P = 0.002) rates, while TBI/CY/CA group demonstrated similar outcomes. Even in the subgroup analyses of disease type or disease risk, the outcomes with intensified conditioning regimens were not superior to those with TBI/CY. In conclusion, although the significant bias has to be carefully considered, the clinical benefit of adding CA or TT to the TBI/CY regimen was not demonstrated.

Predictive value of risk assessment scores in patients with hematologic malignancies undergoing reduced-intensity conditioning allogeneic stem cell transplantation.

Reduced-intensity conditioning allogeneic stem cell transplantation (RIC allo-SCT) is associated with less toxicity and is used for older patients. We retrospectively studied the predictive value of two risk assessment scores, which were the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and the pre-transplantation assessment of mortality (PAM) score, for assessing the outcome of RIC allo-SCT. Seventy-eight patients underwent transplantation between 2005 and 2013 at a single institution. RIC was performed with fludarabine and melphalan with/without total body irradiation. The 3-year overall survival of patients with an HCT-CI >3 was significantly worse than that of patients with an HCT-CI 0-3 (31.6% vs. 59.6%, P = 0.020). Also, the 3-year overall survival of patients with a PAM score >24 was significantly worse than that of those with a PAM score ≤24 (29.2% vs. 61.4%, P = 0.005). The present findings suggest that changing the cut-off values of these risk assessment scores can improve prediction of outcomes in patients receiving RIC allo-SCT with this conditioning regimen and we need validation by large-scale study with other regimens.

Validation of the European Group for Blood and Marrow Transplantation (EBMT) risk score in patients receiving allogeneic hematopoietic stem cell transplantation at a single center in Japan.

We validated the European Group for Blood and Marrow Transplantation (EBMT) risk score in 273 consecutive adult patients receiving allogeneic hematopoietic stem cell transplantation between 2000 and 2010 at our center. The patients were divided into four groups according to the EBMT risk score: low risk (LR, score 0-2), intermediate risk-1 (IR-1, score 3), intermediate risk-2 (IR-2, score 4), and high risk (HR, score 5-7). The five-yr overall survival of the LR (n = 65), IR-1 (n = 67), IR-2 (n = 70), and HR (n = 71) groups was 72%, 57%, 41%, and 25%, respectively (p < 0.001). The five-yr transplant-related mortality rates were 16%, 30%, 25%, and 36%, respectively (p = 0.07). The five-yr cumulative incidence of relapse was 20%, 18%, 37%, and 41%, respectively (p < 0.001). In the subgroup analysis, the prognostic value of the EBMT risk score was confirmed in patients undergoing myeloablative conditioning (MAC), but not in those undergoing reduced-intensity conditioning (RIC). The results suggest that the EBMT risk score is a useful tool to predict transplant outcome for patients undergoing MAC, but not for those undergoing RIC and may be beneficial for stratifying patients in clinical studies.

Human herpesvirus-6 encephalopathy after hematopoietic stem cell transplantation and class I human leukocyte antigen.

Human herpesvirus-6 (HHV-6) encephalopathy is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although reactivation of HHV-6 is often observed after allo-HSCT, encephalopathy only affects a few patients with HHV-6 reactivation. Human leukocyte antigen (HLA) class I is expressed by most somatic cells, and a relationship between some class I alleles and neurological diseases has been reported. The HHV-6 load at two, three, and four weeks after allo-HSCT was examined. HHV-6 encephalopathy was diagnosed from symptoms, results of cerebrospinal fluid examination, and magnetic resonance imaging findings. The relation between HHV-6 reactivation or encephalopathy and the HLA class I status of the recipients was investigated. In 130 patients, 147 allo-HSCT transplantation procedures were carried out. HHV-6 reactivation and encephalopathy occurred in 56 and nine procedures, respectively. HLA mismatch (p = 0.008) and unrelated donor (p = 0.001) were associated with HHV-6 reactivation, but not with HHV-6 encephalopathy. HHV-6 encephalopathy was more frequent in patients with HLA-B*40:06 (p = 0.027). In addition, HLA-A*26:01 and HLA-B*40:06 were found to be associated with each other (p = 0.089), while HLA-B*40:06 and HLA-C*08:01 showed a significant association (p < 0.001). The HLA class I alleles of recipients may be associated with the occurrence of HHV-6 encephalopathy after allo-HSCT.

Clinical significance of pre- and 1-year post-transplant serum ferritin among adult transplant recipients.

To clarify the significance of post-transplant serum ferritin (SF), we retrospectively assessed pre- and post-transplant SF. Among 256 patients undergoing allogeneic stem cell transplant (SCT) for hematologic malignancies between 2000 and 2011, those who had relapsed within 1 year were excluded, and 110 patients surviving for more than 1 year were included in the analysis. The cut-off value of SF was 1000 ng/mL, and four pre- and post-SF groups were defined: low-low (n = 62), low-high (n = 12), high-low (n = 13) and high-high (n = 23). Outcomes at 5 years for each group were as follows: overall survival (OS) 88.2, 38.1, 92.3 and 76.7%, respectively, p = 0.004, and non-relapse mortality (NRM) 11.3, 53.6, 7.7 and 18.9%, respectively, p = 0.037. Patients receiving larger transfusion volumes or developing chronic graft-versus-host disease (GVHD) demonstrated higher 1-year SF values. In multivariate analysis for OS and NRM, low-high SF remained a significant predictor of OS (hazard ratio [HR] = 3.49, 95% confidence interval [CI]: 1.10-11.0, p = 0.032) and NRM (HR = 2.95, 95%CI: 1.04-8.36, p = 0.041). These results suggest that the elevation of SF at 1 year after SCT, which may reflect transfusion and the development of chronic GVHD, may have an aggravating influence on outcomes after SCT. This study provides a clue to clarifying the clinical significance of SF in a transplant setting.

Lymphocyte recovery on day 100 after allogeneic hematopoietic stem cell transplant predicts non-relapse mortality in patients with acute leukemia or myelodysplastic syndrome.

Abstract To clarify the clinical significance of lymphocyte recovery on day 100 after allogeneic hematopoietic stem cell transplant (allo-HSCT), we retrospectively studied 157 patients with hematologic malignancies who underwent allo-HSCT. An absolute lymphocyte count < 500/µL was defined as lymphocytopenia. There was a significant relationship between lymphocytopenia and advanced disease at allo-HSCT or corticosteroid administration within 100 days. Lymphocytopenia on day 100 (hazard ratio [HR]: 2.4; 95% confidence interval [CI]: 1.3-4.5; p = 0.006) and advanced disease at allo-HSCT (HR: 2.2; 95% CI: 1.3-3.9; p = 0.005) were prognostic factors for overall survival by multivariate analysis. Advanced disease was significantly associated with relapse (HR: 2.8; 95% CI: 1.5-5.4; p = 0.002), while lymphocytopenia was an independent predictor of non-relapse mortality (HR: 2.8; 95% CI: 1.1-6.8; p = 0.027). These results suggest that lymphocyte recovery on day 100 may be an important predictor of late complications in patients receiving allo-HSCT for hematologic malignancies.

Recovery of natural killer cells and prognosis after cord blood transplantation.

The relationship between immune reconstitution and the prognosis after cord blood transplantation is unclear. We investigated the influence of natural killer (NK) cell recovery on transplant outcomes. The maximum number of CD56+CD3- cells or CD57+CD16+ cells was determined to assess NK recovery. Although the high CD56+CD3- group and high CD57+CD16+ group showed significantly better overall survival (OS) than the low group on univariate analysis, the high CD57+CD16+ group was associated with better OS on multivariate analysis. These results suggest that CD57+CD16+ cell recovery is more closely related to the outcome after CBT than CD56+CD3- cell recovery.

[Immunophenotypic analysis of hematogones in patients with hematological malignancies].

We studied immunophenotypic analysis of hematogones by flow cytometry. A total of 102 specimens from 93 patients with acute leukemia (52 specimens), myelodysplastic syndromes (4), or malignant lymphoma (46) were analyzed between April and August, 2011. Hematogones were detected in 55 specimens and highly identified in patients with acute myeloid leukemia in remission and B cell lymphoma. Stage 1 (CD34(+)CD20(-)) and stage 2/3 (CD34(-)CD20(+)) were detected in 9.9% and 52.7%, respectively. In addition, the intermediate type (CD34(+)CD20(+)) was identified in 37.4%. All specimens of stage 3 in bright CD45 expression were positive for CD5 and included CD5(+)CD23(-)CD11c(-), 11.1%, CD5(+)CD23(+)CD11c(-), 85.2%, and CD5(+)CD23(+)CD11c(+), 3.7%. These findings suggest that hematogones with unreported immunophenotypes may exist and the appearance of hematogones in hematologic malignancies may be relatively frequent.

[Extramedullary relapse of acute lymphoblastic leukemia in the breast after unrelated allogeneic bone marrow transplantation].

A 28-year-old female presented with an isolated extramedullary relapse in the breast following an unrelated allogeneic bone marrow transplantation(UBMT)for acute lymphoblastic leukemia. She complained of a tumor in her right breast with hematological complete remission 23 months after her first UBMT. The extramedullary lesion resolved with chemotherapy, and she then received a second UBMT. Although there had been no relapse of leukemia in the bone marrow and extramedullary sites, she died from a herpes simplex virus infection in the central nervous system. Extramedullary relapses in the so-called 'sanctuary'sites after hematopoietic stem cell transplantation are unusual, and breast recurrences are even more rare. A treatment strategy for unusual sites of relapse after BMT should be established.

[Immune-mediated encephalomyelitis following varicella-zoster virus infection after allogeneic stem cell transplantation].

A 40-year-old Japanese man with acute myeloid leukemia received allogeneic bone marrow transplantation. On day 101, varicella-zoster virus (VZV) infection occurred, but was improved by administration of acyclovir and immunoglobulin. On day 119, he complained of numbness and double vision, and he was admitted due to exacerbation of the symptoms. The findings of cerebrospinal fluid and magnetic resonance image examination were consistent with the diagnosis of immune-mediated encephalomyelitis (IMEM). Intravenous immunoglobulin therapy was effective and his neurological findings dramatically improved without recurrence. IMEM is a rare non-infectious inflammatory demyelinating disease that can occur after transplantation. We herein describe a case report with a review of the associated literature.

Prognostic factors in patients aged 50 years or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancy.

We retrospectively analyzed patients aged C 50 years with hematologic malignancies who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) to identify preoperative variables predicting the outcome. There were 71 patients with a median age of 57 years (range: 50-63 years) who had acute leukemia (n = 53) or myelodysplastic syndrome (n = 18). Myeloablative conditioning was done in 35 patients and 36 patients had reduced-intensity conditioning. The 5-year overall survival rate (OS), cumulative relapse rate, and non-relapse mortality rate (NRM) were 45, 24, and 33%, respectively. According to multivariate analysis, high-risk disease (HR 3.50, 95% CI 1.43-8.56, P = 0.006), a hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥ 3 (HR 4.41, 95% CI 1.31-14.77, P = 0.016), and an HLA-mismatched unrelated donor (HR 4.03, 95% CI 1.46-11.10, P = 0.007) were significant predictors of worse OS. Highrisk disease was also significantly associated with a higher cumulative relapse rate (HR 4.59, 95% CI 0.94-6.92, P = 0.065). Furthermore, an HCT-CI score ≥ 3 (HR 3.02, 95% CI 1.01-20.78, P = 0.048) and an HLA-mismatched unrelated donor (HR 3.02, 95% CI 1.04-8.74, P = 0.042) were risk factors for NRM. These results suggest that the disease risk, HCT-CI score, and donor type/histocompatibility are prognostic factors for elderly patients, while the conditioning regimen and age are not predictors.

The impact of the dose of natural killer cells in the graft on severe acute graft-versus-host disease after unrelated bone marrow transplantation.

The impact of lymphocyte subpopulations on the outcome of bone marrow transplantation (BMT) remains uncertain. We investigated the relationship between the lymphocyte subpopulations of bone marrow grafts and the outcome of BMT. A total of 121 patients who underwent BMT at Kanagawa Cancer Center between 2000 and 2009 were analyzed. Grade III-IV acute graft-versus-host disease (GVHD) occurred in 35.9% of patients who received unrelated BMT with a CD56 cell dose ≤2.80×10(6)/kg versus only 9.7% of patients with a CD56 cell dose >2.80×10(6)/kg (P=0.017). In patients receiving related BMT, the cumulative incidence of grade III-IV acute GVHD did not differ significantly in relation to the CD56 cell dose. On multivariate analysis, older donor age (hazard ratio (HR): 1.09, 95% confidence interval (CI): 1.03-1.15, P=0.004) and a high dose of CD56 cells (>2.80×10(6)/kg) (HR: 0.15, 95%CI: 0.03-0.92, P=0.040) were significant determinants of grade III-IV acute GVHD after unrelated BMT. None of the lymphocyte subpopulations had a significant impact on the outcome of transplantation, including the rate of neutrophil engraftment, relapse, relapse-free mortality, and overall survival. Our findings suggest that a high natural killer cell dose prevents severe acute GVHD after unrelated BMT, while sparing the graft-versus-leukemia effect.

Pretransplant serum ferritin has a prognostic influence on allogeneic transplant regardless of disease risk.

A multicenter retrospective analysis of the influence of pretransplant serum ferritin (SF) was performed in 261 adult recipients of allogeneic hematopoietic stem cell transplant (allo-HSCT), including 159 patients with acute myeloid leukemia (AML), 66 with acute lymphoid leukemia (ALL) and 36 with myelodysplastic syndrome (MDS). Patients were divided into subgroups according to the pretransplant SF level [< 1000 ng/mL (low) vs. ≥ 1000 ng/mL (high)] and disease status at transplant. A high SF level was significantly associated with high disease risk (p = 0.041), but pretransplant SF and disease risk were independent significant prognostic factors for overall survival (OS), disease-free survival (DFS) and non-relapse mortality rate (NRM) on multivariate analysis. The high-SF group showed a worse outcome than the low-SF group among both standard-risk patients (OS: 54% vs. 64%, p = 0.043; DFS: 46% vs. 57%, p = 0.031) and high-risk patients (OS: 16% vs. 35%, p = 0.001; DFS: 15% vs. 34%, p = 0.001). In conclusion, a high SF at transplant adversely influences the outcome of allo-HSCT regardless of disease risk in patients with acute leukemia and MDS.

[Relationship between early lymphocyte recovery and prognosis after allogeneic hematopoietic stem cell transplantation for acute leukemia in remission].

To assess the relationship between early lymphocyte recovery and outcomes after allogeneic hematopoietic stem cell transplantation (SCT) for acute leukemia in remission, 79 adult patients (AML: 48, ALL: 31) who received transplantation between January 2000 and November 2009 were retrospectively analyzed. The median lymphocyte count on day 30 after SCT (LC30) was 465/µl (range, 10∼2640). On comparison of clinical outcomes between patients with low (LC30<400/µl) and high (LC30≥400/µl) counts, the 5-year overall survival (OS) was significantly better in high LC30 group than in low LC30 group (81.6 vs. 52.6%, p=0.014), but the cumulative relapse rate (RR) and non-relapse mortality (NRM) at 5 years did not differ between the two groups. On multivariate analysis, low LC 30 (HR, 2.44; 95% CI, 1.02∼5.88; p=0.046) and grade II∼IV acute graft-versus-host disease (HR, 2.41; 95% CI, 0.99∼5.90, p=0.0053) were significantly associated with worse OS. However, LC30 was not a risk factor for RR or NRM. These findings suggest that LC30 may be one of the outcome predictors for patients receiving SCT.