Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Potential factors for and the prognostic impact of ascites after allogeneic hematopoietic stem cell transplantation.

Ascites is sometimes detected after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, since limited information is currently available, its clinical meaning remains unclear. Therefore, we herein examined potential factors for and the impact of ascites on the prognosis of patients after allo-HSCT at our institutes. Fifty-eight patients developed ascites within 90 days of allo-HSCT (small in 34 (16%), moderate-large in 24 (11%)). A multivariate analysis identified veno-occlusive disease/sinusoidal obstruction syndrome (p = 0.01) and myeloablative conditioning (p = 0.01) as significant potential factors for the development of small ascites. Thrombotic microangiopathy (TMA) (p < 0.01) was a significant potential factor for moderate-large ascites. The incidence of both small and moderate-large ascites correlated with lower overall survival (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites) and higher non-relapse mortality rates (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites). Lower OS and higher NRM rates correlated with the incidence of both small and moderate-large ascites. Further investigation is warranted to establish whether the clinical sign of ascites improves the diagnostic quality of TMA in a large-scale study.

Prognostic impact of the simple L-index and absolute lymphocyte count early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: The L-index, designed as a quantitative parameter to simultaneously assess the duration and severity of lymphopenia, and absolute lymphocyte count (ALC) have a prognostic impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, discrepancies have been reported in the impact of ALC, and limited information is currently available on the L-index. METHODS: To search for a better clinical tool, the authors retrospectively compared the simple L-index at 30 days (sL-index(30)), which aims to make the original L-index more compact, and ALC at 30 days (ALC(30)) after allo-HSCT in 217 patients who underwent allo-HSCT at the authors' institutions. RESULTS: Median sL-index(30) was 11 712 (range, 4419-18 511) and median ALC(30) was 404 (range, 0-3754). In a multivariate analysis, higher sL-index(30) was associated with a significantly higher cumulative incidence of relapse (CIR) (hazard ratio [HR], 1.01, 95% confidence interval [CI], 1.00-1.02, P = 0.02 for every increase of 100 in sL-index(30)) as well as non-relapse mortality (NRM) (HR, 1.02, 95% CI, 1.00-1.03, P = 0.01 for every increase of 100 in sL-index(30)). Although higher ALC(30) was associated with significantly lower CIR (HR, 0.94, 95% CI, 0.89-1.00, P = 0.04 for every increase of 100/µL in ALC(30)), it was not extracted as an independent risk factor for NRM (HR, 0.96, 95% CI, 0.88-1.05, P = 0.39). Higher sL-index(30) was associated with a slightly higher rate of grade 3-4 acute graft-versus-host disease (GVHD) (HR, 1.02, 95% CI, 1.00-1.04, P = 0.12 for every increase of 100 in sL-index(30)) but not chronic GVHD (HR, 1.00, 95% CI, 0.99-1.01, P = 0.63). ALC(30) was not associated with rates of grade 3-4 acute GVHD (HR, 1.02, 95% CI, 0.88-1.17, P = 0.81) or chronic GVHD (HR, 1.02, 95% CI, 0.98-1.06, P = 0.34). In a receiver operating characteristic curve, the cutoff values of sL-index(30) and ALC(30) for CIR were 9000 and 500, respectively, and the cutoff value of sL-index(30) for NRM was 12 000. CONCLUSIONS: sL-index(30) is a promising tool that may be applied to various survival outcomes. A large-scale prospective study is needed to clarify whether medical interventions based on sL-index(30) values will improve the clinical prognosis of patients.

c-D-index at day 11 can predict febrile neutropenia during chemotherapy in acute myeloid leukemia.

Acute myeloid leukemia (AML) often requires long-term intensive chemotherapy for its cure. During chemotherapy, the patient always experiences neutropenia with readings below 500 cells/µL; this is often accompanied by pyrexia with a temperature of more than 101°F. This combination of neutropenia and fever is called febrile neutropenia (FN). A tool to sum up the daily severity of a patient's neutropenia, the "D-index," has been validated in some specific clinical settings. In this study, we examined whether the D-index is a useful predictor of the onset of FN. We recruited consecutive patients treated with induction and consolidation chemotherapy for newly diagnosed AML. We gathered all the FN events and their clinical background data retrospectively. Patients' background, such as pre-existing conditions and disease status before the treatment, were analyzed using multivariate methods. All FN events during chemotherapy were evaluated for infection focus and causative organism. A total cohort of 51 cases (25 women, 26 men; median age 51 years, range 18-74) was analyzed. They displayed 171 neutropenic events (115 FN and 56 afebrile episodes) during chemotherapy, and complete neutropenic events were used in this study. Sensitivity and specificity analysis showed that the most useful cutoff value to predict the onset of FN was a cumulative D-index at day 11 (c-D11-index) of 718. The cumulative incidence of FN during chemotherapy was significantly higher in the group with c-D11-index ≥710 (80%) than in the group with c-D11-index <710 (39%) (P < 0.0001). Through multivariate analysis, the presence of diabetes mellitus and the c-D11-index were extracted as contributing factors to the onset of FN (P = 0.0087 and 0.0002, respectively). In conclusion, we can predict that AML patients receiving chemotherapy will experience the complication of FN when the c-D-index at day 11 is >710, with an odds ratio of 2.1.

Risk Factors for and the Prognostic Impact of Pericardial Effusion after Allogeneic Hematopoietic Stem Cell Transplantation.

Pericardial effusion (PE) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the mechanisms underlying the onset of PE remain unclear, patients with PE after allo-HSCT have poor clinical outcomes. However, the prognostic impact of PE remains controversial, and risk factors have varied among studies. Therefore, we examined contributing as well as prognostic factors for PE. We retrospectively examined 243 patients who underwent allo-HSCT at the Faculty of Medicine, Kagawa University and Takamatsu Red Cross Hospital, Kagawa, Japan between 2000 and 2020. Forty-three patients (18%) were excluded owing to a lack of data on PE, and thus we ultimately analyzed 200 patients. We reviewed the findings of computed tomography (CT) scans, including chest CT, and echocardiography after allo-HSCT. Only cases in which a radiologist or echocardiography technician detected PE were assessed. PE was stratified into localized PE and whole-circumference PE. The median age at transplantation was 52 years (range, 16 to 74 years). The study cohort comprised 106 patients (53%) age more than 50 years, 88 females (44%), and 112 males (56%). Primary diseases were myeloid neoplasms in 122 patients (61%) and lymphoid neoplasms in 78 (39%). The conditioning regimen was myeloablative in 142 patients (71%) and nonmyeloablative in 58 (29%). The median duration of follow-up was 47 months (range, 1 to 209 months). Forty patients developed PE within 100 days; localized in 23 (12%) and whole circumference in 17 (9%). In a multivariate analysis, significant risk factors for the development of PE within 100 days were late neutrophil engraftment (hazard ratio [HR], 5.24; 95% CI, 1.92 to 14.30; P < .01) and thrombotic microangiopathy (TMA) (HR, 8.23; 95% CI, 1.42 to 47.60; P = .02). The incidence of whole- circumference PE correlated with a lower overall survival (OS) rate (HR, 3.10; 95% CI, 1.34 to 7.17; P < .01) and higher nonrelapse mortality (NRM) rate (HR, 2.94; 95% CI, 1.18 to 7.32; P = .02). In the subgroup analysis, significant risk factors for the development of PE within 365 days were late neutrophil engraftment (HR, 3.13; 95% CI, 1.08 to 9.02; P = .04), the occurrence of chronic graft-versus-host disease (GVHD) (HR, 3.57; 95% CI, 1.19 to 10.70; P = .02), and disease recurrence (HR, 4.98; 95% CI, 1.43 to 17.30; P = .01). The development of whole-circumference PE also correlated with a lower OS rate (HR, 3.83; 95% CI, 1.65 to 8.89; P < .01) and a higher NRM rate (HR, 83.21; 95% CI, 17.75 to 390.10; P < .01). The overall occurrence of acute (grade II to IV) GVHD, chronic GVHD, and TMA were 36% (72 of 200), 39% (78 of 200), and 10% (19 of 200), respectively. In the entire cohort, the 3-year OS rate was 55%, and 3-year relapse and NRM rates were 37 and 14%, respectively. The present results demonstrate that risk factors for PE varied according to the time after allo-HSCT, and that whole-circumference PE at any time correlated with lower OS and higher NRM rates. A large-scale prospective study is needed to verify risk factors for PE and clarify whether immunosuppressive interventions based on the onset of PE improve the clinical prognosis of patients.

c-D-index is a risk factor for prolonged febrile neutropenia during chemotherapy in patients with acute myeloid leukemia.

BACKGROUND: D-index is a recently established clinical tool for assessing neutropenia severity. This study examined whether the D-index can predict the onset of various infections in patients with febrile neutropenia (FN). METHODS: We retrospectively investigated FN events in consecutive patients aged < 65 years who were treated for newly diagnosed acute myeloid leukemia at our institution. We collected data on all FN events during chemotherapy and evaluated the association of FN severity with infectious events. RESULTS: This study included 35 patients (18 women and 17 men; median age, 51 years [range 18-65 years]) with 122 FN events. The response rate to induction chemotherapy was 60% (21/35), and all but one patient survived the treatment. The D-index did not predict FN onset. However, in multivariate analysis, high-dose cytarabine and total D-index were statistically significant explanatory factors for microbiological-proven infections. In addition, multivariate analysis showed that diabetes mellitus is the only risk factor for FN onset. Furthermore, older age, consolidation therapy, and cumulative D-index (c-D-index) were risk factors for prolonged FN. The FN period was the longest in patients with respiratory infections. CONCLUSION: The D-index did not predict the onset of infection. However, FN duration might be prolonged during consolidation therapy in elderly patients with diabetes mellitus, and it is important to manage respiratory infections. These findings indicate the c-D-index is a useful tool to predict prolonged FN.