Maki Hagihara

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.

The SIL index is a simple and objective prognostic indicator in diffuse large B-cell lymphoma

Abstract We previously developed a prognostic index, SIL, which includes advanced stage (S), soluble interleukin-2 receptor level (I), and elevated lactate dehydrogenase level (L) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone (R-CHOP). This time we evaluated the index in a larger cohort and its utility in the risk stratification. The above three factors were independent risk of progression-free survival (PFS). Five-year PFS rates in the standard-risk (SIL index: 0 or 1, nu2009=u2009367) and high-risk groups (SIL index: 2 or 3, nu2009=u2009205) were 79% and 53%, respectively (pu2009<u20090.0001). When the patients were divided by age (≤60 years and >60 years), the SIL index was a good prognostic indicator for PFS in both groups as well as divided by the number of extranodal involvement site (0–1 and >1). The SIL index is a simple and objective prognostic indicator in DLBCL.

Cytomegalovirus Pneumonia after Anti-CC-chemokine Receptor 4 Monoclonal Antibody (Mogamulizumab) Therapy in an Angioimmunoblastic T-cell Lymphoma Patient.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma. A 63-year-old man was diagnosed with AITL. He received 6 cycles of CHOP therapy, but showed progressive disease. Subsequently, he received ESHAP chemotherapy; however, it was not effective. He received mogamulizumab (an anti-CCR4 monoclonal antibody). After 4 cycles, his respiratory condition worsened and he was diagnosed with cytomegalovirus (CMV) pneumonia. Despite antiviral and antibiotic therapy, he died. We speculate that the combination of progressive lymphoma with mogamulizumab and chemotherapy likely caused CMV pneumonia. Because mogamulizumab therapy causes immunosuppression, if CMV pneumonia is suspected, then rapid treatment should be initiated.

Concentrated Ascites Reinfusion Therapy for Sinusoidal Obstructive Syndrome After Hematopoietic Stem Cell Transplantation

Sinusoidal obstruction syndrome (SOS) is one of the severe complications of hematopoietic stem cell transplantation (HSCT). Systemic management including respiratory and circulatory support is necessary. In addition, abdominal paracentesis is often needed for pain relief and to reduce the pressure of tense ascites. Concentrated ascites reinfusion therapy (CART) involves the filtration, concentration, and reinfusion of drained ascites, which contributes to reuse of autologous proteins. CART has been reported as supportive therapy for patients with liver cirrhosis and cancer. We retrospectively reviewed the efficacy and safety of CART in three patients (two with acute myelogenous leukemia and one with chronic myeloid leukemia) who developed SOS after allo-HSCT. They all had symptomatic, tense, and diuretic-refractory ascites with right costal pain and marked weight gain. Two patients showed immediate improvement after CART. However, one patient experienced four CARTs with slow recovery. All patients are now alive and are being monitored as outpatients over 2 years with remission. No severe adverse event was observed related to CART, and 25.2-98.0 (median 30.2) grams of albumin was collected and reinfused. CART after paracentesis reduces protein loss in ascites by reinfusion of autologous protein instead of exogenous albumin preparations. Although transient fever is reported as a frequent adverse event, no events like severe bleeding or infection were observed. While its safety has not been fully established in patients with hematological disease after HSCT, CART may be a considerable supportive therapy for SOS with tense ascites.

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 ≥500u2009×u2009109/L and hemoglobin levels ≥9u2009g/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 ≥500u2009×u2009109/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.

Musculoskeletal pain may be associated with imatinib withdrawal syndrome in chronic myeloid leukemia patients

Chronic myeloid leukemia (CML) is caused by the active BCR-ABL tyrosine kinase resulting from the t(9;22)(q34;q11.2) translocation [1]. Imatinib is a BCR-ABL inhibitor that dramatically improved prognosis in patients with chronic-phase CML [2]. Recently, Rousselot et al . [3] reported that losing the major molecular response (MMR) after imatinib discontinuation is estimated to be 35% at 12 months and 36% at 24 months in the According to Stop Imatinib study (A-STIM); the overall probability of maintaining the complete molecular response (CMR) in patients with stable confi rmed CMR (cCMR) and undetectable cCMR before the study was estimated at 55% and 43%, respectively. It is probable that imatinib can be safely withdrawn. However, the adverse eff ect of discontinuation of imatinib is still unknown. Richter et al . [4] reported that musculoskeletal pain in patients with CML after discontinuation of imatinib is probably associated with withdrawal syndrome. Here, we report fi ve cases in which the patients developed musculoskeletal pain after stopping imatinib. Between February 2014 and March 2015, 13 patients who maintained CMR for at least 2 years were discontinued from using imatinib at Yokohama City University Medical Center. Of the 13 patients, fi ve patients developed musculoskeletal pain with a median onset of 3 months after stopping imatinib. Patient characteristics are summarized in Table I. Th e patients consisted of three men and two women with a median age of 64 years (range x03 51 – 73 years). Th ey achieved MMR and CMR with median times of 9 months (range x03 6 – 18 months) and 9 months (range x03 6 – 38 months), respectively. Th e median years from initiation to discontinuation of imatinib were 97 months (range x03 82 – 107 months). Th ey maintained CMR for a median of 80 months (range x03 34 – 97 months). Th e pain was localized to various parts of the body, especially the limbs and shoulders. C-reactive protein (CRP) was elevated in four patients. Creatine kinase (CK) was elevated in one patient. Orthopedic diseases such as rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) were suspected and the patients were examined by an orthopedist. One patient was examined by a rheumatologist. However, the cause of musculoskeletal pain was unknown. Th e symptoms were grades 1 – 2 according to the Common Terminology Criteria for Adverse Event Scale (version 4.0). Non-steroidal anti-infl ammatory drugs and a poultice were administered for four patients. Clinical symptoms improved gradually in four patients with a median time of 5 months (range x03 2 – 7 months), but not in one of the patients. Th ey did not need steroids. One patient lost CMR (maintained MMR) 9 months after discontinuation of imatinib and dasatinib treatment was initiated.

Intestinal amoebiasis in a patient with acute graft‐versus‐host disease after allogeneic bone marrow transplantation successfully treated by metronidazole

Amoebiasis has rarely been reported in patients undergoing hematopoietic stem cell transplantation, although it is a world‐wide infection and extremely common. We present a case of intestinal amoebiasis unexpectedly revealed by colonoscopy after allogeneic bone marrow transplantation from a human leukocyte antigen‐mismatched unrelated donor for acute myeloid leukemia arising from chronic myelomonocytic leukemia and successfully treated by metronidazole.

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.

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