Center effect on allogeneic hematopoietic stem cell transplantation outcomes for B-cell acute lymphoblastic leukemia.

This nationwide study retrospectively examined the center effect on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia. The cohort analyses were separated into Philadelphia chromosome (Ph)-positive and -negative cases. The patients were divided into low- and high-volume groups according to the number of allo-HSCTs at each facility. The primary endpoint was 5-year overall survival (OS). This study included 1156 low-volume and 1329 high-volume Ph-negative and 855 low-volume and 926 high-volume Ph-positive cases. In Ph-negative cases, 5-year OS was significantly higher in the high-volume centers at 52.7% (95% confidence interval [CI]: 49.9-55.5) versus 46.8% (95% CI: 43.8-49.7) for the low-volume centers (P < 0.01). Multivariate analysis identified high volume as a favorable prognostic factor (hazard ratio [HR]: 0.81 [95% CI: 0.72-0.92], P < 0.01). Subgroup analysis in Ph-negative cases revealed that the center effects were more evident in patients aged ≥40 years (HR: 0.72, 95% CI: 0.61-0.86, P < 0.01) and those receiving cord blood transplantation (HR: 0.62, 95% CI: 0.48-0.79, P < 0.01). In Ph-positive cases, no significant difference was observed between the high and low-volume centers for 5-year OS (59.5% [95% CI: 56.2-62.7] vs. 54.9% [95% CI: 51.3-58.3], P = 0.054). In multivariate analysis, center volume did not emerge as a significant prognostic indicator. This study showed center effects on survival in Ph-negative but not in Ph-positive cases, highlighting the heterogeneity of the center effect in allo-HSCT for B-cell acute lymphoblastic leukemia. Collaborative efforts among transplant centers and further validation are essential to improve outcomes.

RhD mismatch does not affect haematopoietic recovery, graft-versus-host disease and survival in allogeneic haematopoietic cell transplantation: A Japanese registry-based study.

BACKGROUND AND OBJECTIVES: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated. MATERIALS AND METHODS: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database. RESULTS: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis. CONCLUSION: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT.

The effect of center experience on allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia.

This study aimed to address the prognostic impact of center experience based on the data of 7821 adults with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2019 in Japan, where medical care was provided within a uniform healthcare system. Center experience was defined based on the number of allogeneic HCTs performed for any indication during the study period, by which centers were divided into low-, intermediate-, and high-volume centers. After adjusting for known confounding factors, the risk of overall mortality was lowest for the high-volume centers and highest for the low-volume centers, with the difference between the center categories attributed primarily to the risk of relapse. Patients transplanted at high-volume centers had higher risks of acute and chronic graft-versus-host diseases but without an increased risk of non-relapse mortality (NRM). These findings reveal the presence of a center effect in allogeneic HCT conducted during the past decade in Japan, highlighting the difference in relapse based on center experience. The weaker effect on NRM compared with that on relapse suggests that the transplantation care quality is becoming equalized across the country.

Impact of Center Volume on Chronic Graft Versus Host Disease in Patients With Allogeneic Stem Cell Transplantation.

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT), negatively impacting quality of life (QoL) and increasing the risk of death. Complexity in cGVHD diagnosis and treatment causes significant variations in cGVHD management strategies across medical centers and physicians despite the existence of published guidelines. Thus, we hypothesized that center volume is associated with cGVHD incidence and outcomes after cGVHD develops. This study aimed to evaluate the effect of center volume on the incidence of cGVHD in patients who underwent HSCT and outcomes in patients with cGVHD. Our retrospective study included 28,786 patients who underwent their first HSCT (overall cohort) and 7664 who developed cGVHD (cGVHD cohort). We categorized institutions into quartiles (very low, low, high, and very high) using the number of HSCTs performed during the study period. We assessed cGVHD incidence in overall cohort and overall survival (OS) in cGVHD cohort. The very high-volume group showed significantly higher cGVHD incidence (adjusted hazard ratio [HR], 1.38; 95% confidence interval [CI]: 1.30 to 1.46) compared to the very low-volume group. However, the cGVHD incidence was similar among very low-, low- and high-volume groups. Low, high, and very high-volume groups showed significantly higher OS with adjusted HRs of 0.83 (95% CI: 0.73 to 0.94), 0.69 (95% CI: 0.61 to 0.79), and 0.68 (95% CI: 0.60 to 0.76), respectively, compared with the very low-volume group. In conclusion, we revealed a higher incidence of cGVHD in the very high-volume group and a poor survival outcome in the very low-volume group in patients with cGVHD.

Improved Long-Term Net Survival after Allogeneic Hematopoietic Cell Transplantation in Patients with Hematologic Malignancies over Two Decades.

Allogeneic (allo-) hematopoietic cell transplantation (HCT) has evolved as a curative therapy for hematologic malignancies and diseases, with practice changes over the past 2 decades. This study aimed to evaluate the change in 5-year net survival (NS) of allo-HCT recipients in a population-based cohort over the past 2 decades, which allows the estimation of a more HCT-specific long-term survival rate by considering background mortality changes. This study included 42,064 patients with hematologic malignancies who underwent their first allo-HCT in Japan between 2000 and 2018 and were reported to the Transplant Registry Unified Management Program. We compared the 5-year NS after allo-HCT in 4 consecutive HCT periods (2000 to 2004, 2005 to 2008, 2009 to 2012, and 2013 to 2018). The 5-year NS of the latest period was estimated using the period analysis method. Adjusted excess hazard ratios (EHRs) for 5-year NS over the HCT period were analyzed using an EHR model. In addition to the analysis of all hematologic malignancies, adjusted 5-year NS for each major hematologic malignancy, including acute myelogenous leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, adult T cell leukemia/lymphoma, chronic myeloid leukemia (CML), and malignant lymphoma, was analyzed. The probability of adjusted 5-year NS after HCT improved significantly over time: 35% in 2000 to 2004, 39% in 2005 to 2008, 45% in 2009 to 2012, and 49% in 2013 to 2018. The adjusted EHRs were .90 (95% confidence interval [CI], .86 to .93) in the 2005 to 2008 period, .77 (95% CI, .74 to .80) in the 2009 to 2012 period, and .65 (95% CI, .63 to .68) in the 2013 to 2018 period, with the 2000 to 2004 period as the reference. The 5-year NS improved among all hematologic malignancies, with a significant improvement in CML and ALL. The changes in 5-year NS from the 2000 to 2004 period to the 2013 to 2018 period ranged from 46% to 66% in CML and from 41% to 59% in ALL. In addition to the large improvement of 1-year NS, smaller but continued improvement in NS between 1 and 5 years after transplantation was observed. NS at 5 years conditional on being alive at 1 year increased from 64% in 2000 to 2004 to 73% in 2013 to 2018. Even after subtracting the background mortality in the general population, we found a significant improvement in long-term allo-HCT-specific survival rates for patients with hematologic malignancies over the past 2 decades in Japan.

Assessment of cellular response to mitogens in long-term allogeneic hematopoietic stem cell transplantation survivors.

Infection is one of the major causes of death in hematopoietic stem cell transplantation (HSCT) survivors. Precise assessments of immune function after HSCT will be critical in establishing appropriate treatment and prophylaxis, such as re-vaccination. Although several surrogate markers for prediction of clinical outcomes after HSCT have been proposed, definitive markers of immune reconstitution and data on those markers in long-term survivors are lacking. In this study, cellular response to mitogens was assessed and clinical features associated with a poor response to mitogens were investigated in long-term allogeneic HSCT survivors. Age at transplantation and age at the time of mitogen stimulation test were each identified as significant risk factors for poor response to phytohemagglutinin and concanavalin A, respectively (P < 0.001 each). However, time elapsed since transplantation was not found to be correlated with responsiveness to mitogens in this study. Prospective, in-depth studies on immune reconstitution are needed to establish appropriate prophylaxis against infections after HSCT and a schedule for re-vaccination.

The stability of initial tacrolimus concentration following allogeneic hematopoietic stem cell transplantation reduces the risk of acute GVHD.

BACKGROUND: Early tacrolimus (TAC) concentrations correlate with the risk of acute graft-versus-host disease (aGVHD); however, whether the variability of early TAC concentrations after allo-HSCT governs the occurrence of aGVHD remains unknown. Here, we evaluate the correlation between the intrapatient variability (IPV) of initial TAC concentrations and the development of aGVHD. METHODS: We retrospectively assessed 202 patients who underwent allo-HSCT and received standard GVHD prophylaxis by continuous intravenous (iv) infusion of TAC and iv methotrexate. IPV was calculated by using the % coefficient of variation in the initial 4 weeks. RESULTS: With median follow-up duration of 20.7 months, 24 patients were diagnosed with grades II-IV aGVHD. Overall survival (OS) and relapse at 12 months after allo-HSCT were 70.6% (95% confidence interval [CI], 63.7%-76.4%) and 18.9% (95% CI, 13.0%-24.4%), respectively. When IPV was categorized into two groups (high: ≥9.5%; low: <9.5%), the cumulative incidence of grades II-IV aGVHD was greater in the IPV-high group at week 3 (odds ratio: 4.15; 95% CI, 1.37%-12.6%, P = .01). No significant differences were observed in OS and relapse between the two groups. CONCLUSION: We concluded that adjusting early TAC concentration stable may reduce aGVHD after allo-HSCT without affecting the relapse rate.

Prediction of clinical outcome by controlling nutritional status (CONUT) before allogeneic hematopoietic stem cell transplantation in myeloid malignancies.

Malnutrition before allogeneic hematopoietic cell transplantation (allo-HCT) is associated with poor clinical outcomes. Herein, we evaluated the predictive value of controlling nutritional status (CONUT) in patients undergoing allo-HCT for myeloid malignancies. We retrospectively analyzed 200 patients with myeloid malignancies who underwent allo-HCT for the first time. We evaluated CONUT before the initiation of conditioning and compared malnourished patients (poor CONUT, n = 56) with non-malnourished patients (normal CONUT, n = 144). The cumulative incidence of non-relapse mortality within 100 days (early NRM) was significantly higher in the poor CONUT group than in the normal CONUT group [21.4% (95% CI: 11.8-33.0%) vs. 9.7% (95% CI: 5.6-15.2%); P = 0.025]. In multivariate analysis, poor CONUT was an independent and significant risk factor for early NRM [HR: 2.2 (95% CI: 1.0-4.7); P = 0.048]. The overall 1-year survival rate was significantly lower in the poor CONUT group than in the normal CONUT group [53.3% (95% CI: 39.4-65.4%) vs. 71.0% (95% CI: 62.7-77.7%); P = 0.005]. These findings suggest that CONUT before allo-HCT is a useful predictor of poor outcomes in patients with myeloid malignancies.

Higher Peak Tacrolimus Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Increase the Risk of Endothelial Cell Damage Complications.

Noninfectious transplantation-related complications (TRCs) such as graft-versus-host disease (GVHD) and endothelial cell damage (TRC-EC) are critical after allogeneic hematopoietic stem cell transplantation. Tacrolimus (TAC) is used to control GVHD. Hypertension and renal failure are common adverse events after TAC treatment. Higher blood concentrations of TAC would be expected to reduce the risk of GVHD but may increase TRC-EC. TRC-EC often develops in patients with GVHD; thus, it is difficult to clinically determine the proper intensity of immunosuppression. We therefore evaluated the impact of weekly mean/peak TAC blood concentrations (PTCs) on TRC-EC occurrence and prognosis. Patients (N = 295) who received TAC as a GVHD prophylaxis at our institute from 2009 to 2016 were eligible for this retrospective study. Forty-three patients were diagnosed with TRC-EC: 8 with sinusoidal obstructive syndrome, 28 with transplant-associated microangiopathy, and 7 with idiopathic pneumonia syndrome. The cumulative incidence of TRC-EC at 12 months was 13.8% (95% confidence interval [CI] 10.1% to 18.1%). After multivariate analysis high PTCs during days 22 to 28 (hazard ratio [HR] 2.47; 95% CI, 1.37 to 4.45; P < .01) and grades II to IV acute GVHD (HR, 5.61; 95% CI, 2.99 to 10.53; P < .01) were associated with TRC-EC occurrence. The probability of overall survival (OS) at 12 months was 67.7% (95% CI, 61.7% to 73.0%). After multivariate analysis TRC-EC diagnosis (HR, 2.47, 95% CI, 1.59 to 3.83; P < .01) and high-risk disease (HR, 1.75; 95% CI, 1.17 to 2.61; P < .01) were significantly associated with poor OS. In conclusion, higher PTC during days 22 to 28 increased the risk of TRC-EC. TRC-EC development was associated with poor OS.