Satomi Ito

Pretransplant serum ferritin is associated with bloodstream infections within 100 days of allogeneic stem cell transplantation for myeloid malignancies

We retrospectively studied the association between iron overload and bloodstream infections (BSI) in the 100-day period following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia or myelodysplastic syndromes. Serum ferritin was measured before transplantation to evaluate iron overload. Of 114 adult patients who underwent transplantation between 2000 and 2008, 36 (32%) developed BSI. Of the 44 isolates, 63% were Gram-positive bacteria, 32% were Gram-negative bacteria, and 4% were fungi. The median time to the onset of the first BSI was day 28 (range day 0–95) after transplantation. Univariate analysis revealed a significantly higher incidence of BSI in the high (≥1,000 ng/ml, n = 57) than in the low (<1,000 ng/ml, n = 57) ferritin group (42.1 versus 21.1%, respectively, P = 0.017). Peripheral blood stem cell transplantation (PBSCT) (n = 23) showed a greater protective effect against BSI compared with bone marrow (n = 71) and cord blood (n = 20) transplantation. Pretransplantation serum ferritin (HR = 2.844, 95% CI: 1.180–6.859, P = 0.020) and PBSCT (HR = 0.135, 95% CI: 0.025–0.717, P = 0.019) were significant factors on multivariate analysis. In conclusion, pretransplantation serum ferritin significantly predicts BSI within the 100-day period after allo-HSCT.

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

Abstract 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.

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

Abstract 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.

R-CHOP therapy alone for limited-stage follicular lymphoma

Irradiation therapy alone is a standard strategy for limited-stage FL, leading to a 10-year progression-free survival (PFS) rate of 30-50%. However, we have been administering R-CHOP therapy alone to patients with limited-stage FL. A total of 35 patients with newly diagnosed FL received R-CHOP therapy with curative intent between 2002 and 2009. The median age of the 35 patients was 61 years; 7 patients had in CS 1 FL, and 28 patients, CS 2 FL. The median number of R-CHOP cycles was 6. On completion of the R-CHOP therapy, 33 patients achieved complete response and 1 showed partial response (PR). The patient showing PR after the completion of R-CHOP was administered additional irradiation. The remaining 1 patient was not evaluated because of discontinuation of hospital visit. In all the 35 patients, the 5-year PFS rate was 70%, and the 5-year overall survival rate was 92%. In the 15 patients with a PFS>5 years, only 1 patient showed disease progression. The outcome of R-CHOP therapy alone in patients with limited-stage FL was at least equivalent to the reported outcome of irradiation therapy alone. R-CHOP therapy could be an alternative to irradiation therapy in limited-stage FL patients.

Acute leukemia during pregnancy: an investigative survey of the past 11 years

The management of pregnant women with acute leukemia is usually challenging. We collected data concerning pregnant women with acute leukemia in the Kanagawa area in Japan.

Myeloablative hematopoietic stem cell transplantation for myelodysplastic syndrome in patients younger than 55 years: impact of comorbidity and disease burden on the long‐term outcome

We retrospectively investigated 31 myelodysplastic syndrome (MDS) patients receiving myeloablative hematopoietic stem cell transplantation (HCT) and focused on prognostic factors affecting the long‐term outcome. Patients were classified according to the French‐American‐British classification and the HCT‐comorbidity index was determined. Cytosine arabinoside or thiotepa combined with cyclophosphamide and total body irradiation was used as myeloablative conditioning in eight and 23 patients respectively. After a follow‐up period of 0.8–14.2 years from transplantation (median: 6.4 years), 23 patients were alive in complete remission, and the 5‐year overall survival (OS) and disease‐free survival (DFS) rates were 79% and 72% respectively. The cumulative nonrelapse mortality (NRM) rate was 22% at 5 years. According to multivariate analysis, ≥20% blasts in the bone marrow and an HCT‐comorbidity score ≥ 3 were significantly associated with poor OS and DFS. Patients with a high HCT‐comorbidity score and male patients receiving transplantation from female donors were significantly more likely to have a higher NRM according to the univariate, but not the multivariate analysis. These data suggest that comorbidity and the tumor burden at the time of transplantation may be useful variables for predicting the outcome in MDS patients receiving myeloablative HCT.

Cerebral venous sinus thrombosis after allogeneic stem cell transplantation

Neurological complications are an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT) [1]. Complications that affect the central nervous system (CNS) can include infection in immunocompromised hosts, cerebrovascular events such as subdural hematoma or stroke, calcineurin-induced CNS neuropathy, and leukoencephalopathy resulting from intrathecal chemotherapy or cranial irradiation [2]. Cerebral venous sinus thrombosis (CVST) is a relatively rare complication after allogeneic HSCT [3, 4] and its pathogenesis is still unclear. Here, we describe a patient who developed CVST during immunosuppressive therapy for chronic graft-versus-host disease (GVHD) after allogeneic HCST. In August 2007, a 42-year-old Japanese woman was diagnosed as having acute myeloid leukemia. She was transferred to our hospital for allogeneic HSCT in January 2008, after achieving complete remission with combination chemotherapy. In March 2008, the patient underwent allogeneic HSCT from her HLA-identical brother. The pretransplant conditioning regimen consisted of intravenous busulfan (0.8 mg/m 9 4/day on days -7, -6, -5, and -4) and cyclophosphamide (60 mg/kg/day on days -3 and -2). She received GVHD prophylaxis with short-term methotrexate (15 mg/m on day 1; and 10 mg/m on days 3 and 6) plus cyclosporin A (CsA) as a continuous infusion at a dose of 3 mg/kg/day. She also received 250 lg/day of granulocyte colony-stimulating factor by continuous infusion from day 1 to promote granulocyte recovery. Her granulocyte count was more than 0.5 9 10/L on day 19 and the platelet count exceeded 20 9 10/L on day 26. Complete engraftment was confirmed on day 22 by fluorescence in situ hybridization analysis using Xand Y-chromosome probes. She developed acute GVHD (grade II) involving the skin on day 26 and was treated with a topical corticosteroid preparation. She was discharged on day 87 without any evidence of GVHD. However, she was re-admitted on day 120 after HSCT because of skin lesions and a decrease of the platelet count. A diagnosis of chronic GVHD with skin lesions (maculopapular rash, sclerotic changes, and abnormal pigmentation) and thrombocytopenia (21 9 10/L) was made, and prednisolone (PSL) was started at a dose of 0.5 mg/kg daily from day 126. Although her skin lesions improved, recovery of the platelet count was not obtained. Bone marrow smear on day 135 revealed hypocellular marrow and a few megakaryocytes. Examination of the clotting profile on day 141 showed the following: her prothrombin time was 65% (normal range 70–130%), the fibrinogen level was 85 mg/dL (normal range 150–450 mg/dL), the FDP level was 31.1 lg/dL (normal range 0–5.0 lg/dL), the D-dimer level was 11.1 lg/dL (normal range 0–1.0 lg/dL), and the thrombomodulin level was 4.0 FU/mL (normal range 0–1.0 FU/mL). Lactate dehydrogenase level was within normal limits and fragmented red cells were not observed. Thrombosis was suspected from the laboratory findings, but deep vein thrombosis was not detected by screening tests. On day 153, she suddenly developed a severe K. Motohashi (&) T. Tachibana H. Takasaki M. Tanaka A. Maruta H. Kanamori Department of Hematology, Kanagawa Cancer Center, 1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan e-mail: motohashik@kcch.jp

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. &NA; The clinical significance of ferritin at diagnosis in patients with acute myeloid leukemia was examined in a multicenter retrospective study. Elevated ferritin may indicate tumor burden and predict worse event‐free survival in the high‐risk karyotype group.

The presence of mature granulocytes/monocytes derived from leukemic cells in MLL-associated leukemia

We observed the mature granulocytes/monocytes derived from leukemic cells in patients with acute myeloid leukemia who present mixed lineage leukemia gene (MLL). Morphologic observation and fluorescence in situ hybridization analysis (FISH) for chromosome 11q23 abnormality were studied, and a multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was done to identify the fusion partners with MLL. The bone marrow cells with FISH signals of MLL showed the cell differentiation of the myeloid and/or monocytic lineages in 4 of 6 AML patients. MLL partner genes were AF6, AF9, ELL, and ENL, respectively. There was no correlation between the fusion partner and the appearance of mature cells derived from MLL clones. RT-PCR showed the fusion between MLL exon 9 or 10 and the partner genes in mature granulocytes/monocytes. These findings suggest that subgroup of leukemia cells with MLL rearrangement has the differentiation potential of leukemic cells and mature granulocytes/monocytes derived from MLL clones may be biologically different from normal mature cells.