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.

Metabolic Steal of the Myocardium by Primary Cardiac Lymphoma.

Less than 1.0% of malignant lymphomas are primary cardiac lymphoma (PCL), a rare malignant lymphoma. Due to its infrequency, the metabolic dynamics of the treatment have not been completely analyzed. A 62-year-old man who had been complaining of exertional dyspnea for a month arrived at our emergency room. He developed right cardiac failure as a result of a mass in the right atrium, according to a computed tomography (CT) scan. According to an echocardiogram, the mass was obstructing his blood flow and affecting how his heart worked. The lump was pathologically determined to be diffuse large B-cell lymphoma after he underwent urgent heart surgery. The lesion was only localized in the heart, according to a postoperative 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/CT scan, indicating that the disease was in clinical stage IE. An 18F-FDG-PET/CT scan showed a thickness of the right atrial wall as residual disease despite the majority of the cardiac lymphomatous mass being removed during surgery; it also showed that the usual uptake of 18F-FDG in healthy myocardium had diminished. Following chemotherapy, 18F-FDG uptake recovered in the patient's normal myocardium of the heart in remission. In conclusion, a sort of "metabolic steal phenomenon" that may be connected to PCL is the difference in uptake between tumor-involved and healthy myocardium.

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.

Distinct Characteristics of Sweet's Syndrome of the Scrotum Caused by All-trans Retinoic Acid in a Patient with Acute Promyelocytic Leukemia.

Induction therapy with all-trans retinoic acid (ATRA) is effective for acute promyelocytic leukemia (APL). ATRA induces neutrophil differentiation and its associated side effects. The differentiation syndrome is the most characterized ATRA-induced adverse effect. Sweet's syndrome, also known as neutrophilic dermatosis, is another form of ATRA-associated disease characterized by neutrophil infiltrating erythema that develops with fever. This is a case of a 34-year-old Japanese man diagnosed with APL. At the onset, the patient did not have skin involvement of APL cells. He was treated with ATRA and induction chemotherapy with idarubicin and cytarabine. Scrotal skin rash occurred at day 14, which developed into scrotal ulceration up to day 28 even after eliminating APL cells in his peripheral blood. Sweet's syndrome is a pathological diagnosis of scrotal skin ulceration representing neutrophil infiltration. The infiltrating neutrophils showed PML-RARα rearrangement. The patient was diagnosed with ATRA-associated Sweet's syndrome with skin ulcer. His cutaneous lesion did not respond to intravenous prednisolone therapy; thereby, ATRA was discontinued. After the cessation of ATRA, the skin lesion improved in the next week. We confirmed he achieved a complete response after induction chemotherapy. In our observation, ATRA-associated Sweet's syndrome is characterized by the following clinical manifestations: preferable occurrence in the scrota, tend to progress into skin ulcer, and pathogenicity associated with PML-RARα-positive matured neutrophils. The etiology, pathogenesis, and risk factors of ATRA-associated scrotal ulceration were discussed in the literature review.

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.

A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation.

Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.

Diagnostic Value of Flow Cytometry Standardized Using the European LeukemiaNet for Myelodysplastic Syndrome.

BACKGROUND: Myelodysplastic syndromes (MDS) and idiopathic cytopenia of undetermined significance (ICUS) are heterogeneous hematological disorders characterized by hematopoietic dysplasia and/or chromosomal aberrancy. OBJECTIVES: This study aimed to evaluate the diagnostic value of flow cytometry standardized using the European LeukemiaNet (ELN) for MDS and ICUS by analyzing samples obtained from patients with cytopenia based on morphological examination, cytogenetic analysis, and flow cytometry. METHODS: We retrospectively analyzed bone marrow samples aspirated from 253 consecutive patients (median age: 66 years [range: 1-92]) to identify the cause of cytopenia. RESULTS: Sixty patients presented with MDS, and 16 with ICUS. MDS subtypes were distributed as follows: MDS with single-lineage dysplasia (n = 10); MDS with multi-lineage dysplasia (n = 10); MDS with ringed sideroblasts (n = 4); MDS with excess blasts-1 (n = 9); MDS with excess blasts-2 (n = 13), MDS unclassified (n = 5); 5q-syndrome (n = 6); and MDS/myeloproliferative neoplasms (n = 3). Four representative ELN indexes were used. Two or more ELN MDS indexes were in the abnormal range in 35 MDS cases (58.3%) and 4 ICUS cases (25.0%). CONCLUSIONS: Morphological examination remains the standard for MDS diagnosis. Considering the low incidence of genetically proven ICUS (20.2-27.5%), the low sensitivity of ELN MDS indexes for ICUS is considered a valuable alternative.

Nonclonal chromosomal alterations and poor survival in cytopenic patients without hematological malignancies.

BACKGROUND: Clonal chromosomal alterations (CCAs) reflect recurrent genetic changes derived from a single evolving clone, whereas nonclonal chromosomal alterations (NCCAs) comprise a single or nonrecurrent chromosomal abnormality. CCAs and NCCAs in hematopoietic cells have been partially investigated in cytopenic patients without hematological malignancies. METHODS: This single-center retrospective study included 253 consecutive patients who underwent bone marrow aspiration to determine the cause of cytopenia between 2012 and 2015. Patients with hematological malignancies were excluded. CCA was defined as a chromosomal aberration detected in more than two cells, and NCCA was defined as a chromosomal aberration detected in a single cell. RESULTS: The median age of the patients was 66 years. There were 135 patients without hematological malignancies (median age, 64 years; 69 females); of these, 27 patients (median age, 69 years; 8 females) harbored chromosomal abnormalities. CCAs were detected in 14 patients; the most common CCA was -Y in eight patients, followed by inv.(9) in three patients and mar1+, inv. (12), and t (19;21) in one patient each. NCCAs were detected in 13 patients; the most frequent NCCA was +Y in four patients, followed by del (20), + 8, inv. (2), - 8, and add (6) in one patient each. Moreover, nonclonal translocation abnormalities, including t (9;14), t (14;16), and t (13;21), were observed in three patients. One patient had a complex karyotype in a single cell. The remaining 106 patients with normal karyotypes comprised the control group (median age, 65 years; range, 1-92 years; 56 females). Further, follow-up analysis revealed that the overall survival of the NCCA group was worse than that of the CCA and the normal karyotype groups (P < 0.0001; log-rank test).The survival of the NCCA-harboring cytopenic patients was worse than that of the CCA-harboring cytopenic patients without hematological malignancies, suggesting that follow-up should be considered for both CCA- and NCCA-harboring cytopenic 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.

Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Løken syndrome.

Senior Løken syndrome (SLS) is a heterogeneous disorder characterized by severe retinal degenerations and juvenile-onset nephronophthisis. Genetic variants in ten different genes have been reported as the causes of SLS. Clinical evaluation of a patient with SLS and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218 + 3insT and c.1631A > G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218 + 3insT variant leads to exon 14 skipping (p.V383_M406del), while the other variant (c.1631A > G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts (6 bps deletion in the last of exon 17 [p.V543_K544del] and exons 17 and 18 skipping [p.D480E, S481_K610del]). Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein. In conclusion, we identified compound heterozygous splice site variants of SCLT1 in a patient with a new form of ciliopathies that exhibits clinical features of SLS.

Surgery for gastroesophageal reflux disease with Gaucher disease type 2.

Gaucher disease, the most common lysosomal storage disease, is sometimes complicated with gastroesophageal reflux disease (GERD). The present patient was a 136-day-old Japanese boy with Gaucher disease type 2. Enzyme replacement therapy and chemical chaperone therapy were successful for the skin disorders, joint contractures, hepatosplenomegaly and thrombocytopenia, but he also had GERD. Accordingly, a Nissen fundoplication with gastrostomy was performed. There was no vulnerability of organs, easy bleeding or difficulty of maintaining the visual field because of hepatosplenomegaly during operation. In the perioperative period, there was no prolonged wound healing or infection. GERD was improved. In the near future, the number of long-term survivors of Gaucher disease will increase due to improvements in medical therapy. Therefore, it is expected that the number of patients requiring fundoplication will also increase. In patients with successful medical therapy, surgical fundoplication can be safely and effectively performed.

Is yolk sac tumor related to the pathophysiology of low birthweight?

An 8-year-old Japanese girl was admitted with an ovarian yolk sac tumor. Regarding birth history, the patient had been delivered by cesarean section at 25 weeks of gestation with a birthweight of 711g. She had required neonatal intensive care including oxygenation, various medications, and tests. After surgery and chemotherapy, there was no recurrence for 2 years, at the time of writing. Yolk sac tumor, which is a malignant germ cell tumor, is rare in children. Although the cause and risk factors are unclear, it has been reported that malignant germ cell tumors in childhood have been associated with pathophysiology at birth. Given that premature infants are more likely to survive due to advances in perinatal care, it is expected that such cases will increase in the near future. We suggest that children born prematurely require careful follow up.

Persistent Left Superior Vena Cava in Hematological Malignancy Requiring Central Venous Catheter Insertion for Intensive Chemotherapy.

Persistent left superior vena cava is a congenital vascular anomaly, which is possibly arrhythmogenic and thrombogenic, rarely complicated with coronary sinus atresia. We treated a 42-year-old male with Hodgkin's lymphoma requiring central venous catheter placement for intensive chemotherapy. Persistent left superior vena cava was revealed after the insertion of the central venous catheter by the radiological finding of the catheter tip cannulated into the vena cava cavity. The relationship between coronary sinus atresia and persistent left superior vena cava induced by central venous catheterization remains unclear; however, the hematologist should pay attention to the malpositioning of the central venous catheter.