Investigation of biomarkers to predict outcomes in allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Various biomarkers have been developed and evaluated to predict the prognosis and complications of allogeneic hematopoietic cell transplantation (HCT). Most previous studies conducted on different biomarkers evaluated single effects such as those associated with inflammation, immunology, iron metabolism, and nutrition, and only a few studies have comprehensively analyzed markers. OBJECTIVE: The study aimed to survey comprehensive multiple markers prior to HCT and extract those that significantly predict the outcomes. STUDY DESIGN: A prospective multicenter observational study was performed. (UMIN000013506) Patients undergoing HCT for hematologic diseases were consecutively enrolled. Besides the usual clinical biomarkers, serum samples for extra-clinical biomarkers were collected and cryopreserved before starting the conditioning regimen. A total of 32 candidate biomarkers were selected, 23 from hematology, biochemistry, immunology, nutrition, and iron metabolism, and 9 from composite markers. Based on the area under the curve (AUC) values for survival, promising biomarkers was extracted. Internal validation for these markers was applied based on bootstrap methods. Setting the cut-off values for them, log-rank test was applied and outcomes including overall survival (OS), relapse, and non-relapse mortality (NRM) were evaluated using multivariate analyses. Furthermore, detailed analysis including transplant-related complications and external validation were conducted focusing on C-reactive protein (CRP) to platelet (Plt) ratio. RESULTS: A total of 152 patients with hematologic malignancies were enrolled from April 2014 to March 2017. CRP, soluble interleukin-2 receptor (IL2R), CRP to albumin (Alb) ratio, CRP to Plt ratio, Plt to IL2R ratio, and IL2R to Alb ratio were identified as promising markers. Internal validation successfully confirmed their reliability of AUC and multivariate analysis demonstrated the statistical significance between the higher and the lower markers. Above all, a higher CRP to Plt ratio was significantly associated with a lower OS (hazard ratio [HR] 2.77; 95% confidence interval [CI] 1.30-5.91; P = 0.008) and higher non-relapse mortality rates (HR 2.79; 95%CI 1.14-6.80; P = 0.024) at 180 days. Furthermore, univariate analysis showed that a higher CRP to Plt ratio was significantly associated with a higher incidence of sinusoidal obstructive syndrome (P < 0.001) and bloodstream infection (P = 0.027). An external validation test confirmed the significance of the CRP to Plt ratio for these outcomes. CONCLUSION: The multicenter prospective observational study successfully identified significant biomarkers in patients with hematologic malignancies who received HCT. In particular, CRP to Plt ratio was identified as a novel and useful biomarker for predicting transplant outcomes. Further investigations are needed to validate the novel markers, analysis of the pathophysiology, and application to treatment settings other than HCT.

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.

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.

R-CHOP therapy alone in limited stage diffuse large B-cell lymphoma.

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone.

Clinical manifestations of primary pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in Japanese population.

We retrospectively analysed 16 cases of newly diagnosed pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma in the Japanese population. The disease was found on the basis of examination findings in 14 cases, and clinical manifestations in 2. According to the extensive staging procedure, four patients had concomitant gastric involvement. Primary treatment involved surgery alone in two patients; surgery followed by rituximab (R)-containing chemotherapy in two; R-containing chemotherapy alone in 11; and chemoradiotherapy without R in one. Over the median observation period of 28 months, disease progression was recorded in three patients, but all 16 patients were alive at the end of the observation period. One patient was treated with R alone and achieved partial remission; subsequent tentative surgery showed no evidence of residual lymphoma. It has been 72 months of progression-free survival after the diagnosis. Primary pulmonary MALT lymphoma exhibited an indolent clinical course. R has potential as a therapeutic agent in patients with pulmonary MALT lymphoma.

Clinical features of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue.

We newly diagnosed 131 patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue lymphoma between 1998 and 2010. We retrospectively studied 124 patients for whom complete clinical data were available at presentation and who had minimally undergone tumour staging by physical examination, computed tomography (CT), bone marrow aspiration, and biopsy. A slight female predominance (men, 58; women, 66) was observed in the study population; the median age was 67 years. The primary locations at presentation were the stomach (38%), orbita (20%), lung (12%), intestinal tract (8%), thyroid gland (6%), others (14%), and unknown (2%). Seventy per cent of patients had localized disease. Of the 124 patients, 14 (11%) had lymph node involvement, and 5 (4%) had bone marrow involvement. Five (4%) patients had both lung and gastric involvement. The 5-year overall survival rate for the 124 patients was 96.1%. The overall vital prognosis was excellent. Moreover, gastro-intestinal fiberscopic examination is essential, especially in cases with lung involvement at presentation.

[POEMS syndrome treated with lenalidomide plus high-dose dexamethasone as a pre-transplant induction therapy].

A 60-year-old male with POEMS syndrome received lenalidomide and high-dose dexamethasone combination therapy as an initial treatment, with no severe adverse events occurring during the treatment. Two cycles of the therapy led to significantly decreased serum VEGF level, and IgA-λ type M-protein was not detected by immunofixation electrophoresis. We next performed autologous stem cell transplantation, without severe complications such as engraftment syndrome. He improved enough to walk independently and now is being followed up without treatment. This case suggests that lenalidomide-dexamethasone therapy is highly effective and can be a good option for pre-transplant treatment for POEMS syndrome.

Impact of graft sources on immune reconstitution and survival outcomes following allogeneic stem cell transplantation.

We evaluated the kinetics of immune reconstitution (IR) after allogeneic hematopoietic cell transplantation (HSCT) and analyzed the clinical effect of IR on posttransplant outcomes. Absolute lymphocyte and its subset counts were measured using flow cytometry on days 28, 100, 180, 365, and 730 after transplantation in 358 adult patients who underwent HSCT between 2009 and 2017. On day 100 after HSCT, 310 surviving patients were analyzed. Bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT) were performed in 119, 55, and 136 patients, respectively. Mature B-cell and differentiated natural killer (NK) cell subset counts significantly increased after CBT. The 2-year overall survival (OS), nonrelapse mortality (NRM), cumulative incidence of relapse, and chronic GVHD in BMT, PBSCT, and CBT were 62%, 67%, and 76% (P = .021); 17%, 17%, and 13% (P = .82); 33%, 40%, and 27% (P = .063); and 43%, 45%, and 28% (P = .025), respectively. Multivariate analysis showed that higher CD16+CD57- NK cell counts correlated with lower disease relapse, whereas higher CD20+ B-cell counts correlated with lower NRM. OS-favoring factors were higher CD16+CD57- NK cell count (hazard ratio, 0.36; 95% confidence interval, 0.22-0.60; P < .001) and CD20+ B-cell count (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P < .001) and lower Disease Risk/HCT-Specific Comorbidity index score. Collective contribution of graft source-specific and event-related immune reconstitution might yield better posttransplant outcomes in CBT.

Computed tomography-defined sarcopenia: prognostic predictor of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study.

We analyzed clinical cutoffs for defining computed tomography (CT) methods for sarcopenia and examined the prognostic value of CT for allogeneic hematopoietic stem cell transplantation (allo-HCST) outcomes of patients with myeloid malignancy. One hundred twenty-five adult patients with acute myeloid leukemia and myelodysplastic syndrome who underwent first allo-HSCT between 2000 and 2017 were included. Sarcopenia was assessed using CT-based skeletal muscle index (SMI) and mean muscle attenuation at L3. A statistical difference in SMI was confirmed between sarcopenia (n = 52) and nonsarcopenia (n = 73) patients. There were no significant correlations of muscularity with age, performance status, or other characteristics of HSCT. After 2 years, overall survival (OS) was 43.5% and 70.1%, disease-free survival was 52.9% and 68.6%, nonrelapse mortality (NRM) was 20.8% and 8.4%, incidence of acute GVHD (≥ grade 2) was 38.8% and 39.1%, that of chronic GVHD was 53.2% and 37.3%, and median duration of hospitalization was 88 days and 74 days (P = 0.026), respectively, in the sarcopenia and nonsarcopenia groups. Multivariate analysis showed that presence of sarcopenia is a novel adverse factor for high NRM and poor OS. Pretransplant CT-defined sarcopenia is correlated with decreased OS, increased NRM, and prolonged hospitalization.

Impact of treatment-related weight changes from diagnosis to hematopoietic stem-cell transplantation on clinical outcome of acute myeloid leukemia.

We hypothesized that treatment-related weight loss is associated with worse outcomes following HSCT. Overall, 184 patients with AML who underwent induction therapy were classified according to d-BMI (BMI at transplant minus BMI at diagnosis) (kg/m2) as < -2, - 2 to + 2, and > + 2. At 1 year, OS was 67.9% (95% CI, 60.7-74.2), DFS was 64.1% (95% CI, 56.7-70.6), and GRFS was 40.2% (95% CI, 33.1-47.2). For d-BMI groups < - 2, - 2 to + 2, and > + 2, GRFS at 1 year was 16.1% (95% CI, 5.1-31.4), 45.4% (95% CI, 36.4-53.7), and 41.7% (95% CI, 22.2-60.1), respectively (P = 0.0067). Multivariate analysis showed that both worse OS (HR, 1.78; 95% CI, 1.02-3.14; P = 0.007) and GRFS (HR, 2.34; 95% CI, 1.26-4.35; P = 0.007) were associated with reduced BMI (d-BMI < - 2). Treatment-related weight reduction in AML was associated with poor outcome after HSCT.

Clinical Significance of Serum Ferritin at Diagnosis in Patients With Acute Myeloid Leukemia: A YACHT Multicenter Retrospective Study.

PURPOSE: A multicenter retrospective analysis was performed to evaluate the clinical significance of serum ferritin at diagnosis in patients with acute myeloid leukemia (AML). METHODS: The study cohort included 305 patients who were newly diagnosed with AML from 2000 to 2015 and received standard induction chemotherapy. Transplantation was performed in 168 patients. RESULTS: The median ferritin value was 512 ng/mL (range, 8-9475 ng/mL). Ferritin correlated with lactate dehydrogenase, C-reactive protein, white blood cell count, and blast count, and elevation of ferritin was associated with poor performance status. The median follow-up period was 58 months (range, 4-187 months) among survivors. The high ferritin group (≥ 400 ng/mL) demonstrated inferior event-free survival (EFS) at the 5-year interval (30% vs. 40%; P = .033) compared to the low ferritin group. Multivariate analysis in the high-risk karyotype revealed that high ferritin levels predicted worse EFS (hazard ratio = 2.07; 95% confidence interval, 1.28-3.33; P = .003). CONCLUSION: Elevated ferritin at diagnosis may indicate tumor burden in patients with AML and predict worse EFS in the high-risk group.

Outcome and prognostic factors among patients who underwent a second transplantation for disease relapse post the first allogeneic cell transplantation.

The prognosis for disease relapse after first hematopoietic cell transplantation (HCT1) is poor. Here, we present a retrospective multicenter study to evaluate the clinical outcome and the prognostic factors for second hematopoietic cell transplantation (HCT2). The cohort in this study comprised 60 patients diagnosed with acute leukemia, who underwent HCT2 due to hematological relapse after HCT1. The overall survival (OS) at two years, non-relapse mortality (NRM), and relapse mortality (RM) were 30.3%, 40.9%, and 28.8%, respectively. Multivariate analysis for OS identified the use of a donor other than matched-related (MR) donor (hazard ratios [HR] = 4.10, 95% confidence intervals [CI]: 1.72-9.74, p = .001) and high disease status (HR = 2.90, 95% CI: 1.28-6.56, p = .011) as the adverse risk factors for HCT2. On analyzing the combination of factors during HCT1 and HCT2, MR donor, reduced intensity conditioning regimen, and standard status were found to be significant as favorable prognostic factors for OS. Therefore, evaluating these prognostic factors would be helpful in taking decisions regarding post-relapse management.

Body mass index is a prognostic factor in adult patients with acute myeloid leukemia.

Body mass index (BMI), which represents the proportion of weight to height, is a controversial prognostic factor for acute myeloid leukemia (AML). We evaluated prognostic value of BMI in Japanese AML. The study included 369 adult patients with newly diagnosed AML who were administered either daunorubicin or idarubicin with cytarabine as induction chemotherapy. The patients were categorized into two groups according to their BMI: the NW group (BMI < 25.0 kg/m2; normal and underweight) and OW group (BMI ≥ 25.0 kg/m2; overweight and obese). We analyzed treatment efficacy and toxicity of induction chemotherapy, and survival outcomes in each group. Patients in the OW group showed a better complete remission rate than the NW group (86.1 versus 76.5%, P = 0.045), no early death (0.0 versus 4.1%, P = 0.042), and better overall survival (OS) at 3 years (62.2 versus 50.1%, P = 0.012). Multivariate analysis showed BMI is an independent prognostic factor for OS (hazard ratio 0.62, 95% confidence interval 0.42-0.92, P = 0.017). These results indicate the prognostic value of BMI in adult AML patients.

Hyper-recovery of platelets after induction therapy is a predictor of relapse-free survival in acute myeloid leukemia.

We verified the association between standard clinical and laboratory variables and the risk of relapse in acute myeloid leukemia (AML), which led us to retrospectively examine the effect of regeneration of hematopoiesis in patients with newly diagnosed AML. We used data from 230 patients who obtained remission after cytarabine-based induction chemotherapy. Platelet counts ≥500 × 109/L and hemoglobin levels ≥9 g/dL on day 28 after treatment initiation were significantly associated with relapse-free survival (RFS) rate, conferring respective multivariate risk ratios of 0.38 (95% CI: 0.18-0.79) and 0.60 (95% CI: 0.40-0.89) for the occurrence of relapse or death. No disease relapse occurred in core binding factor leukemia patients whose platelet counts recovered ≥500 × 109/L at 28 days after therapy initiation. We conclude that regeneration of hematopoiesis, especially platelet hyper-recovery, after induction chemotherapy is a significant predictor of RFS in patients with AML.

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.

Prognostic index for relapsed acute leukemia after allogeneic stem cell transplant.

We retrospectively studied patients who relapsed after allogeneic stem cell transplantation (SCT) to identify factors influencing outcomes. Of the 296 patients (196 with AML and 100 with ALL), 102 (34%) experienced relapse at a median of 222 days (range: 30-2,748) after SCT. Multivariable analysis showed that high disease risk (hazard risk [HR]: 1.95; 95% confidence interval [CI]: 1.17-3.24; p = 0.010), unrelated donor (HR: 1.76; 95% CI: 1.10-2.80; p = 0.018), and interval of < 180 days from SCT to relapse (HR: 2.10; 95% CI: 1.26-3.51; p = 0.004) were independent factors of 2-year post-relapse survival (PRS). These factors were used as a prognostic index for PRS. The 2-year PRS in patients of score 0, score 1, score 2, and score 3 was 38%, 19%, 3%, and 0%, respectively (p < 0.001). Our new prognostic index may be helpful for selecting the treatment for relapsed patients after SCT.

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.

Serum ferritin level is prognostic of patient outcome in extranodal NK/T cell lymphoma, nasal type.

The objective of the current study was to assess the prognostic factors in patients with extranodal natural killer (NK)/T cell lymphoma, nasal type (ENKL). We retrospectively analyzed 35 patients who were diagnosed with ENKL between 1998 and 2011. The median patient age was 63 years, and the male/female ratio was 22:13; twenty patients had localized ENKL, and 26 had a good Eastern Cooperative Oncology Group performance status (score 0 or 1). B symptoms were present in 17 patients. Twenty-five patients presented with nasal or paranasal lesions, or both. With a median follow-up duration among patients still alive at their last follow-up of 47 months (range 8-93 months), the 3-year overall survival (OS) rate was 44.5 %. Multivariate analysis revealed that advanced disease stage (P = 0.002), the presence of extranasal disease (P = 0.013), and serum ferritin levels greater than 300 ng/ml (P < 0.001) were significant and independent (negative) prognostic factors. High serum ferritin levels were associated with the presence of B symptoms, elevated lactate dehydrogenase levels, and high soluble interleukin-2 receptor levels, but not with clinical stage. Patients with high ferritin levels had a remarkably low remission rate (23 %) and a short OS time (median: 4 months). Serum ferritin level at the time of diagnosis of ENKL was a useful prognostic factor.

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.